Cyclic Amine Azaheterocyclic Carboxamides

ABSTRACT

The invention provides novel cyclic amine azaheterocyclic carboxamide according to Formula (I), Formula (II) and Formula (III) their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

FIELD OF THE INVENTION

The invention relates to a series of cyclic amine azaheterocycliccarboxamide compounds that are useful in the treatment ofhyperproliferative diseases, such as cancer, in mammals. Alsoencompassed by the present invention is the use of such compounds in thetreatment of hyperproliferative diseases in mammals, especially humans,and pharmaceutical compositions containing such compounds.

SUMMARY OF THE RELATED ART

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a wide variety of signaltransduction processes within the cell (Hardie, G. and Hanks, S. (1995)The Protein Kinase Facts Book. I and II, Academic Press, San Diego,Calif.). The kinases may be categorized into families by the substratesthey phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,lipids, etc.). Sequence motifs have been identified that generallycorrespond to each of these kinase families (e.g., Hanks, S. K., Hunter,T., FASEB J., 9:576-596 (1995); Knighton, et al., Science, 253:407-414(1991); Hiles, et al., Cell, 70:419-429 (1992); Kunz, et al., Cell,73:585-596 (1993); Garcia-Bustos, et al., EMBO J., 13:2352-2361 (1994)).

Protein kinases may be characterized by their regulation mechanisms.These mechanisms include, for example, autophosphorylation,transphosphorylation by other kinases, protein-protein interactions,protein-lipid interactions, and protein-polynucleotide interactions. Anindividual protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cell processes including, but notlimited to, proliferation, differentiation, apoptosis, motility,transcription, translation and other signalling processes, by addingphosphate groups to target proteins. These phosphorylation events act asmolecular on/off switches that can modulate or regulate the targetprotein biological function. Phosphorylation of target proteins occursin response to a variety of extracellular signals (hormones,neurotransmitters, growth and differentiation factors, etc.), cell cycleevents, environmental or nutritional stresses, etc. The appropriateprotein kinase functions in signalling pathways to activate orinactivate (either directly or indirectly), for example, a metabolicenzyme, regulatory protein, receptor, cytoskeletal protein, ion channelor pump, or transcription factor. Uncontrolled signalling due todefective control of protein phosphorylation has been implicated in anumber of diseases, including, for example, inflammation, cancer,allergy/asthma, diseases and conditions of the immune system, diseasesand conditions of the central nervous system, and angiogenesis.

Protein kinase 70S6K, the 70 kDa ribosomal protein kinase p70S6K (alsoknown as SK6, p70/p85 S6 kinase, p70/p85 ribosomal S6 kinase andpp70S6K), is a member of the AGC subfamily of protein kinases. p70S6K isa serine-threonine kinase that is a component of thephosphatidylinositol 3 kinase (PI3K)/AKT pathway. p70S6K is downstreamof PI3K, and activation occurs through phosphorylation at a number ofsites in response to numerous mitogens, hormones and growth factors.p70S6K activity is also under the control of a mTOR-containing complex(TORC1) since rapamycin acts to inhibit p70S6K activity. p70S6K isregulated by PI3K downstream targets AKT and PKCζ. Akt directlyphosphorylates and inactivates TSC2, thereby activating mTOR. Inaddition, studies with mutant alleles of p70S6K that inhibited byWortmannin but not by rapamycin suggest that the PI3K pathway canexhibit effects on p70S6K independent of the regulation of mTORactivity.

The enzyme p70S6K modulates protein synthesis by phosphorylation of theS6 ribosomal protein. S6 phosphorylation correlates with increasedtranslation of mRNAs encoding components of the translational apparatus,including ribosomal proteins and translational elongation factors whoseincreased expression is essential for cell growth and proliferation.These mRNAs contain an oligopyrimidine tract at their 5′ transcriptionalstart (termed 5′TOP), which has been shown to be essential for theirregulation at the translational level.

In addition to its involvement in translation, p70S6K activation hasalso been implicated in cell cycle control, neuronal celldifferentiation, regulation of cell motility and a cellular responsethat is important in tumor metastases, the immune response and tissuerepair. Antibodies to p70S6K abolish the mitogenic response driven entryof rat fibroblasts into S phase, indication that p70S6K function isessential for the progression from G1 to S phase in the cell cycle.Furthermore, inhibition of cell cycle proliferation at the G1 to S phaseof the cell cycle by rapamycin has been identified as a consequence ofinhibition of the production of the hyperphosphorylated, activated formof p70S6K.

A role for p70S6K in tumor cell proliferation and protection of cellsfrom apoptosis is supported based on it participation in growth factorreceptor signal transduction, overexpression and activation in tumortissues. For example, Northern and Western analyses revealed thatamplification of the PS6K gene was accompanied by correspondingincreases in mRNA and protein expression, respectively (Cancer Res.(1999) 59: 1408-11-Localization of PS6K to Chromosomal Region 17q23 andDetermination of Its Amplification in Breast Cancer).

Chromosome 17q23 is amplified in up to 20% of primary breast tumors, in87% of breast tumors containing BRCA2 mutations and in 50% of tumorscontaining BRCA1 mutations, as well as other cancer types such aspancreatic, bladder and neuroblastoma (see M. Barlund, O. Monni, J.Kononen, R. Cornelison, J. Torhorst, G. Sauter, O.-P. Kallioniemi andKallioniemi A., Cancer Res., 2000, 60:5340-5346). It has been shown that17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K,and SIGMA1B genes (Cancer Res. (2000): 60, pp. 5371-5375).

The p70S6K gene has been identified as a target of amplification andoverexpression in this region, and statistically significant associationbetween amplification and poor prognosis has been observed.

Clinical inhibition of p70S6K activation was observed in renal carcinomapatients treated with CCI-779 (rapamycin ester), an inhibitor of theupstream kinase mTOR. A significant linear association between diseaseprogression and inhibition of p70S6K activity was reported.

In response to energy stress, the tumor suppressor LKB1 activates AMPKwhich phosphorylates the TSC1/2 complex and enables it to inactivate themTOR/p70S6K pathway. Mutations in LKB1 cause Peutz-Jeghers syndrome(PJS), where patients with PJS are 15 times more likely to developcancer than the general population. In addition, ⅓ of lungadenocarcinomas harbor inactivating LKB1 mutations.

p70S6K has been implicated in metabolic diseases and disorders. It wasreported that the absence of p70S6K protects against age- anddiet-induced obesity while enhancing insulin sensitivity. A role forp70S6K in metabolic diseases and disorders such as obesity, diabetes,metabolic syndrome, insulin resistance, hyperglycemia,hyperaminoacidemia, and hyperlipidmia is supported based upon thefindings.

Compounds described as suitable for p70S6K inhibition are disclosed inWO 03/064397, WO 04/092154, WO 05/054237, WO 05/056014, WO 05/033086, WO05/117909, WO 05/039506, WO 06/120573, WO 06/136821, WO 06/071819, WO06/131835, WO 08/140947 and PCT/US10/000313.

DESCRIPTION OF THE INVENTION

It is the object of the present invention to provide novel p70S6Kinhibitors useful in the treatment of hyperproliferative diseases,especially those related to the hyperactivity of the above mentionedprotein kinases, such as cancer in mammals, with superiorpharmacological properties both with respect to their activities as wellas their solubility, metabolic clearance and bioavailabilitycharacteristics.

As a result, this invention provides novel, cyclic amine azaheterocyliccarboxamide compounds and pharmaceutically acceptable salts, solvates orprodrugs thereof, that are kinase inhibitors and useful in the treatmentof the above mentioned diseases.

The compounds are defined by Formula (I):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof,wherein:

-   X is N or C—R³,-   Y is N, NH or is absent,-   R¹ is L¹-R⁴-L²-R⁵-L³-R⁶, L¹-R⁴-L²-R⁵ or L¹-R⁴,-   R² is A, Hal, OH, OA, SH, CN, NH₂, NO₂, NHA, NH-L¹-Ar, NHCOA,    NHCO-L¹-Ar, NHSO₂A, NHSO₂-L¹-Ar, NHCONHA, NHCONH-L¹-Ar, L¹-Ar,    O-L¹-Ar, L¹-R⁴ or H,-   L¹, L³ each, independently of one another is a single bond,    methylene, or methyl substituted methylene, wherein the methylene,    or the methyl group of the methyl substituted methylene may be    unsubstituted or mono- or disubstituted with Hal, OH, CN, NH₂,    NH(LA), N(LA)₂, NO₂, COOH, N₃, ethenyl or ethynyl, and/or    monosubstituted with R⁴, and in which one or two CH₂ groups may be    replaced by an O or S atom or by an —NH—, —N(LA)-, —CONH—,    —N(LA)COO—, —SO₂— or —NHCO— group,-   R³ is H, A, Hal, OH, COOH, SH, NH₂, NO₂ or CN, R⁴, R⁵, R⁶ each,    independently of one another, are Ar, or cyclic A which may be mono-    or disubstituted by Hal or LA,-   L² is —NHCO—, —NHCOO—, —NHCONH—, —NHCONA-, —NHCOA-, —O—, —S—, —NH—,    —NHSO₂—, —SO₂NH—, —CONH—, —CONHCONH—, —NHCONHCO—, or -A-,-   Ar is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1,    2, 3 or 4 N, O and/or S atoms and 5, 6, 7, 8, 9, or 10 skeleton    atoms, which may be unsubstituted or, independently of one another,    mono-, di- or trisubstituted by Hal, A, OH, SH, OA, NH₂, NHA, NA₂,    NO₂, CN, OCN, SCN, COOH, COOA, CONH₂, CONHA, CONA₂, NHCOA, NHCONHA,    NHCONH₂, NHSO₂A, CHO, COA, SO₂NH₂, SO₂A and/or SO₂Hal, and in which    a ring N-atom may be substituted by an O-atom to form an N-oxide    group,    -   and in which in the case of a bicyclic aromatic cycle on of the        two rings may be partly saturated,-   A is unbranched or branched linear or cyclic alkyl having 1, 2, 3,    4, 5, 6, 7 or 8 C atoms, in which one or two CH₂ groups may be    replaced by an O or S atom and/or by an —NH—, —CO—, —NHCOO—,    —NHCONH—. —N(LA)-, —CONH—, —NHCO— or —CH═CH— group, and in which 1-3    H atoms may be replaced by Hal, and in which one or two CH₃ groups    may be replaced by OH, SH, NH₂, NH(LA), N(LA)₂, NHCOOH, NHCONH₂ or    CN,-   LA is unbranched or branched, linear alkyl having 1, 2, 3 or 4 C    atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal and-   Hal is F, Cl, Br or I.

In general, all residues which occur more than once may be identical ordifferent, i.e. are independent of one another. Above and below, theresidues and parameters have the meanings indicated for the Formula (I),unless expressly indicated otherwise.

Accordingly, the invention relates, in particular, to the compounds ofthe Formula (I) in which at least one of the said residues has one ofthe preferred meanings indicated below.

“Hal” denotes fluorine, chlorine, bromine or iodine, in particularfluorine or chlorine.

“A” denotes, for example, methyl, furthermore ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-,2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl,hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl. “A” furtherdenotes alkyl as defined above, in which one or two CH₂ groups may bereplaced by O or S atoms and/or by NH, N(LA), CONH, NHCO or—CH═CH-groups and/or in addition 1-3 H atoms may be replaced by F and/orCl, such as, for example, trifluoromethyl, pentafluoroethyl,1,1-difluoromethyl, 1,1,1-trifluoroethyl, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

In other examples of “A”, one or two CH₃ groups is replaced by OH, SH,NH₂, N(LA)H, N(LA)₂ or CN, such as, for example,N,N′-dimethylaminoalkyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl,5-aminopentyl, 3-aminomethylcyclobutyl or cyanoalkyl. Cyclic Apreferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl.

“LA” denotes unbranched or branched, linear alkyl having 1, 2, 3 or 4 Catoms, wherein 1, 2 or 3 H atoms may be replaced by Hal, e.g. methyl,ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

“Ar” denotes, for example, unsubstituted phenyl, naphthyl or biphenyl,furthermore preferably, for example, phenyl, naphthyl or biphenyl, eachof which is mono-, di- or trisubstituted by A, fluorine, chlorine,bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy,hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl,amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy,sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido,butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxyl,methoxycarbonyl, ethoxycarbonyl, aminocarbonyl.

“Ar” furthermore denotes phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p-aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-di-methylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)-phenyl,further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl,(4-methoxyphenyl)methyl, (3-methoxyphenyl)methyl,(4-methoxyphenyl)ethyl, (3-methoxyphenyl)ethyl. “Ar” furthermorepreferably denotes 2-, 3- or 4-phenyl, 2-, 3- or 4-phenylmethyl, 2-, 3-or 4-phenylethyl, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl,1-, 2,4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridylmethyl, 2-, 3-or 4-pyridylethyl, 2-, 4-, 5- or 6-pyrimidinyl, 2-, 3-, 5-, or6-pyrazin-1- or 4-yl, furthermore preferably 1,2,3-triazol-1-, -4- or-5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl,1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3-or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, 1-, 2-, 3-,4-, 5-, 6- or 7-indolyl, 2-, 3-, 4- or 5-isoindolyl, 2-, 6, - or8-purinyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 1-, 3-, 4-,5-, 6-, 7- or 8-isoquinolinyl, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, quinoxalin-2-, 3-, 4- or 5-yl, 4-, 5-,or 6-phthalazinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl,

further preferably 1,3-benzodioxol-2-, 4- or 5-yl, thiophen-2- or 3-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or2,1,3-benzoxadiazol-5-yl, furan-2- or 3-yl, 2,3-dihydro-benzofuran-2-,3-, 4- or 5-yl,each of which is unsubstituted or may be mono-, di- or trisubstituted,for example, by carbonyl oxygen, F, Cl, Br, methyl, ethyl, propyl,phenyl, benzyl, —CH₂-cyclohexyl, hydroxyl, methoxy, ethoxy, amino,methylamino, dimethylamino, nitro, cyano, carboxyl, methoxycarbonyl,aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, acetamino,ureido, methylsulfonylamino, formyl, acetyl, aminosulfonyl and/ormethylsulfonyl.

In those cases where R¹ is L¹-R⁴-L²-R⁵, residue R⁴ obviously has abridging function, and is substituted by linkers L¹ and L²,independently of any further substitutions it may have.

The term “substituted” preferably relates to the substitution by theabove-mentioned substituents, where a plurality of different degrees ofsubstitution are possible, unless indicated otherwise.

All physiologically acceptable salts, derivatives, solvates, solvates ofsalts, and stereoisomers of these compounds, including mixtures thereofin all ratios, are also in accordance with the invention.

The compounds of the Formula (I) may have one or more centres ofchirality. They may accordingly occur in various enantiomeric forms andbe in racemic or optically active form. The invention therefore alsorelates to the optically active forms (stereoisomers), the enantiomers,the racemates, the diastereomers and hydrates and solvates of thesecompounds.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

An elegant method for the resolution of racemates containing estergroups (for example acetyl esters) is the use of enzymes, in particularesterases.

In a preferred group of compounds of Formula (I) the variables andsubstituents have the following meanings:

-   X is N,-   Y is NH,-   R¹ is L¹-R⁴-L²-R⁵,-   R² is LA, Hal, OH, O(LA), SH, CN, NH₂, NO₂, NH(LA), NHCO(LA),    NHSO₂(LA), NHCONH(LA),-   L¹, L³ is methyl substituted methylene, wherein the methyl group of    the methyl substituted methylene is monosubstituted with NH₂ or    NH(LA), N(LA)₂, or cyclic A which may be mono- or disubstituted by    Hal or LA,-   R⁴, R⁵ is a monocyclic aromatic homo- or heterocycle having 0, 1 or    2 N, O and/or S atoms and 5 or 6 skeleton atoms, which may be    unsubstituted or, independently of one another, mono-, di- or    trisubstituted by Hal, A, OH, SH, OA, NH₂, NHA, NA₂, NO₂, CN, OCN,    SCN, COOH, COOA, CONH₂, CONHA, CONA₂, NHCOA, NHCONHA, NHCONH₂,    NHSO₂A, CHO, COA, SO₂NH₂, SO₂A and/or SO₂Hal,-   L² is —NHCO—, —NHCOO—, —NHCONH—, —NHCONA-, —NHCOA-, —O—, —S—, —NH—,    —NHSO₂—, —SO₂NH—, —CONH—, —CONHCONH—, —NHCONHCO—, or -A-,-   A is unbranched or branched linear or cyclic alkyl having 1, 2, 3,    4, 5, 6, 7 or 8 C atoms, in which one or two CH₂ groups may be    replaced by an O or S atom and/or by an —NH—, —CO—, —NHCOO—,    —NHCONH—. —N(LA)-, —CONH—, —NHCO— or —CH═CH— group, and in which 1-3    H atoms may be replaced by Hal, and in which one or two CH₃ groups    may be replaced by OH, SH, NH₂, NH(LA), N(LA)₂, NHCOOH, NHCONH₂ or    CN,-   LA is unbranched or branched, linear alkyl having 1, 2, 3 or 4 C    atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal and-   Hal is F, Cl, Br or I.

In preferred embodiments, the compounds of the present invention aredescribed by Formula (II) and Formula (III), and pharmaceuticallyacceptable salts, solvates, solvates of salts, or prodrugs thereof, inwhich the residue identifiers which overlap with Formula (I) have thesame definitions as in Formula (I), i.e., X and R², while the balance ofthe residue identifiers, i.e., Y′, Z and Z′, are defined below:

wherein,

-   Y′ is CH2 or NH such that when Y′ is NH, Z is CH2 (or absent) and    when Y′ is CH2, Z is NH,-   Z is CH2, NH or is absent such that when Z is CH2 (or absent), Y is    NH and when Z is NH, Y is CH2 and-   Z′ is Ar, alkyl, halogen, OR, NRR, CF3, CN, OCF3, SR or H (mono, di,    or tri-substituted with any above combination).

The compounds of the present invention can be in the form of a prodrugcompound. “Prodrug compound” means a derivative that is converted into abiologically active compound according to the present invention underphysiological conditions in the living body, e.g., by oxidation,reduction, hydrolysis or the like, each of which is carried outenzymatically, or without enzyme involvement. Examples of prodrugs arecompounds, wherein the amino group in a compound of the presentinvention is acylated, alkylated or phosphorylated, e.g.,eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein thehydroxyl group is acylated, alkylated, phosphorylated or converted intothe borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy,fumaryloxy, alanyloxy or wherein the carboxyl group is esterified oramidated, or wherein a sulfhydryl group forms a disulfide bridge with acarrier molecule, e.g. a peptide, that delivers the drug selectively toa target and/or to the cytosol of a cell. These compounds can beproduced from compounds of the present invention according to well-knownmethods. Other examples of prodrugs are compounds, wherein thecarboxylate in a compound of the present invention is for exampleconverted into an alkyl-, aryl-, choline-, amino, acyloxymethylester,linolenoyl-ester.

Metabolites of compounds of the present invention are also within thescope of the present invention.

Where tautomerism, e.g., keto-enol tautomerism, of compounds of thepresent invention or their prodrugs may occur, the individual forms,e.g., the keto or the enol form, are claimed separately and together asmixtures in any ratio. The same applies for stereoisomers, e.g.,enantiomers, cis/trans isomers, conformers and the like. If desired,isomers can be separated by methods well known in the art, e.g. byliquid chromatography. The same applies for enantiomers, e.g., by usingchiral stationary phases. Additionally, enantiomers may be isolated byconverting them into diastereomers, i.e., coupling with anenantiomerically pure auxiliary compound, subsequent separation of theresulting diastereomers and cleavage of the auxiliary residue.Alternatively, any enantiomer of a compound of the present invention maybe obtained from stereoselective synthesis using optically pure startingmaterials.

The compounds of the present invention can be in the form of apharmaceutically acceptable salt or a solvate. The term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids, includinginorganic bases or acids and organic bases or acids. In cases where thecompounds of the present invention contain one or more acidic or basicgroups, the invention also comprises their correspondingpharmaceutically or toxicologically acceptable salts, in particulartheir pharmaceutically utilizable salts. Thus, the compounds of thepresent invention which contain acidic groups can be present in saltform, and can be used according to the invention, for example, as alkalimetal salts, alkaline earth metal salts or as ammonium salts. Moreprecise examples of such salts include sodium salts, potassium salts,calcium salts, magnesium salts or salts with ammonia or organic aminessuch as, for example, ethylamine, ethanolamine, triethanolamine or aminoacids. Compounds of the present invention which contain one or morebasic groups, i.e. groups which can be protonated, can be present insalt form, and can be used according to the invention in the form oftheir addition salts with inorganic or organic acids. Examples ofsuitable acids include hydrogen chloride, hydrogen bromide, phosphoricacid, sulfuric acid, nitric acid, methanesulfonic acid,p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, aceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, and other acids known tothe person skilled in the art. If the compounds of the present inventionsimultaneously contain acidic and basic groups in the molecule, theinvention also includes, in addition to the salt forms mentioned, innersalts or betaines (zwitterions). The respective salts can be obtained bycustomary methods which are known to a person skilled in the art, forexample by contacting these with an organic or inorganic acid or base ina solvent or dispersant, or by anion exchange or cation exchange withother salts. The present invention also includes all salts of thecompounds of the present invention which, owing to low physiologicalcompatibility, are not directly suitable for use in pharmaceuticals butwhich can be used, for example, as intermediates for chemical reactionsor for the preparation of pharmaceutically acceptable salts.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Many compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. For example, if thesolvent is water the solvate formed is a hydrate, when the solvent isalcohol, the solvate formed is an alcoholate, if the solvent is anether, the solvate formed is an etherate. Specific examples of solvatesinclude mono- or dihydrates, methanolates, ethanolates ordiethyletherates.

Those skilled in the art appreciate that in many cases the solvates ofpharmaceutical active ingredients, or their pharmaceutically acceptablesalts, are used in pharmaceutical compositions, and know how to obtainsuch solvates.

Furthermore, the present invention relates to pharmaceuticalcompositions comprising a compound of the present invention, or aprodrug compound thereof, or a pharmaceutically acceptable salt orsolvate, or a solvate of such salt, as an active ingredient togetherwith a pharmaceutically acceptable carrier.

“Pharmaceutical composition” means one or more active ingredients, andone or more inert ingredients that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the present invention may additionallycomprise one or more other compounds as active ingredients, such as oneor more additional compounds of the present invention, or a prodrugcompound or other p70S6K inhibitors.

The pharmaceutical compositions include compositions suitable for oral,rectal, topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In one embodiment, said compounds and pharmaceutical composition are forthe treatment of cancer such as brain, lung, colon, epidermoid, squamouscell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney,liver, ovarian, prostate, colorectal, uterine, rectal, oesophageal,testicular, gynecological, thyroid cancer, melanoma, hematologicmalignancies such as acute myelogenous leukemia, multiple myeloma,chronic myelogenous leukemia, myeloid cell leukemia, glioma, Kaposi'ssarcoma, or any other type of solid or liquid tumors. Preferably, thecancer to be treated is chosen from breast, colorectal, lung, prostateor pancreatic cancer or glioblastoma.

The invention also relates to the use of compounds according to theinvention for the preparation of a medicament for the treatment ofhyperproliferative diseases related to the hyperactivity of p70S6K aswell as diseases modulated by the p70S6K cascade in mammals, ordisorders mediated by aberrant proliferation, such as cancer andinflammation.

The invention also relates to a compound or pharmaceutical compositionfor treating a disease related to vasculogenesis or angiogenesis in amammal which comprises a therapeutically effective amount of a compoundof the present invention, or a pharmaceutically acceptable salt, prodrugor solvate thereof, and a pharmaceutically acceptable carrier.

In one embodiment, said compound or pharmaceutical composition is fortreating a disease selected from the group consisting of tumorangiogenesis, chronic inflammatory disease such as rheumatoid arthritis,inflammatory bowel disease, atherosclerosis, skin diseases such aspsoriasis, eczema, and sclerodema, diabetes, diabetic retinopathy,retinopathy of prematurity and age-related macular degeneration.

This invention also relates to a compound or pharmaceutical compositionfor inhibiting abnormal cell growth in a mammal which comprises anamount of a compound of the present invention, or a pharmaceuticallyacceptable salt or solvate or prodrug thereof, in combination with anamount of another anti-cancer therapeutic, wherein the amounts of thecompound, salt, solvate, or prodrug, and of the chemotherapeutic aretogether effective in inhibiting abnormal cell growth. Many anti-cancertherapeutics are presently known in the art. In one embodiment, theanti-cancer therapeutic is a chemotherapeutic selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.In another embodiment the anti-cancer therapeutic is an antibodyselected from the group consisting of bevacizumab, CD40-specificantibodies, chTNT-1/B, denosumab, zanolimumab, IGF1R-specificantibodies, lintuzumab, edrecolomab, WX G250, rituximab, ticilimumab,trastuzumab and cetuximab. In yet another embodiment the anti-cancertherapeutic is an inhibitor of another protein kinase, such as Akt, Axl,Aurora A, Aurora B, dyrk2, epha2, fgfr3, igf1r, IKK2, JNK3, Vegfr1,Vegfr2, Vegfr3 (also known as Flt-4), KDR, MEK, MET, Plk1, RSK1, Src,TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK,PDGFR, TAK1, LimK, Flt-3, PDK1 and Erk.

This invention further relates to a method for inhibiting abnormal cellgrowth in a mammal or treating a hyperproliferative disorder thatcomprises administering to the mammal an amount of a compound of thepresent invention, or a pharmaceutically acceptable salt or solvate orprodrug thereof, in combination with radiation therapy, wherein theamounts of the compound, salt, solvate, or prodrug, is in combinationwith the radiation therapy effective in inhibiting abnormal cell growthor treating the hyperproliferative disorder in the mammal. Techniquesfor administering radiation therapy are known in the art, and thesetechniques can be used in the combination therapy described herein. Theadministration of a compound of the invention in this combinationtherapy can be determined as described herein. It is believed that thecompounds of the present invention can render abnormal cells moresensitive to treatment with radiation for purposes of killing and/orinhibiting the growth of such cells.

Accordingly, this invention further relates to a method for sensitizingabnormal cells in a mammal to treatment with radiation which comprisesadministering to the mammal an amount of a compound of the presentinvention or pharmaceutically acceptable salt or solvate or prodrugthereof, which amount is effective is sensitizing abnormal cells totreatment with radiation. The amount of the compound, salt, or solvatein this method can be determined according to the means for ascertainingeffective amounts of such compounds described herein. The invention alsorelates to a method for inhibiting abnormal cell growth in a mammal thatcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, a prodrug thereof,or an isotopically-labeled derivative thereof, and an amount of one ormore substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents.

In practical use, the compounds of the present invention can be combinedas the active ingredient in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like. In the case of oral liquidpreparations, any of the usual pharmaceutical media may be employed,such as, for example, suspensions, elixirs and solutions; or carrierssuch as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. In the case of oral solid preparations the composition may takeforms such as, for example, powders, hard and soft capsules and tablets,with the solid oral preparations being preferred over the liquidpreparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of the present invention may also be administeredparenterally. Solutions or suspensions of these active compounds can beprepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils.

Under ordinary conditions of storage and use, these preparations containa preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds of thepresent invention are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating or preventing cancer, inflammation or other proliferativediseases for which compounds of the present invention are indicated,generally satisfactory results are obtained when the compounds of thepresent invention are administered at a daily dosage of from about 0.01milligram to about 100 milligram per kilogram of animal body weight,preferably given as a single daily dose. For most large mammals, thetotal daily dosage is from about 0.1 milligrams to about 1000milligrams, preferably from about 0.2 milligram to about 50 milligrams.In the case of a 70 kg adult human, the total daily dose will generallybe from about 0.2 milligrams to about 200 milligrams. This dosageregimen may be adjusted to provide the optimal therapeutic response.

The invention also relates to a set (kit) consisting of separate packsof:

a) an effective amount of a compound according to the invention or aphysiologically acceptable salt, solvate or prodrug thereof, andb) an effective amount of a further medicament active ingredient.The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound according tothe invention and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

EXPERIMENTAL SECTION

Some abbreviations that may appear in this application are as follows:

Abbreviations Designation ACN acetonitrile ATP Adenosine triphosphate bBroad peak d Doublet DMSO dimethylsulfoxide DIEAN,N-Diisopropylethylamine DTT dithiothreitol EDTAEthylenediaminetetraacetic acid equiv. equivalents Et ethyl h hour HEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPLC High pressureliquid chromatography LC/MS Liquid chromatography coupled to massspectrometry m multiplet M Molecular ion m/z Mass-to-charge ratio Memethyl min minute MS Mass spectrometry N Normal (unit of concentration)NMO 4-methylmorpholine N-oxide NMR Nuclear Magnetic Resonance PGProtecting group psi Pounds per square inch q Quartette (or quartet) RfRetention factor RT Room temperature Rt. Retention time s Singlet TertTertiary TEA Triethylamine TFA Trifluoroacetic acid THABTetrahexylammonium bromide THF Tetrahydrofuran UV ultraviolet VISvisible

The compounds of the present invention can be prepared according to theprocedures of the following Schemes and Examples, using appropriatematerials and are further exemplified by the following specificexamples.

Moreover, by utilizing the procedures described herein, in conjunctionwith ordinary skills in the art, additional compounds of the presentinvention claimed herein can be readily prepared. The compoundsillustrated in the examples are not, however, to be construed as formingthe only genus that is considered as the invention. The examples furtherillustrate details for the preparation of the compounds of the presentinvention. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds.

The instant compounds are generally isolated in the form of theirpharmaceutically acceptable salts, such as those described above. Theamine-free bases corresponding to the isolated salts can be generated byneutralization with a suitable base, such as aqueous sodiumhydrogencarbonate, sodium carbonate, sodium hydroxide and potassiumhydroxide, and extraction of the liberated amine-free base into anorganic solvent, followed by evaporation. The amine-free base, isolatedin this manner, can be further converted into another pharmaceuticallyacceptable salt by dissolution in an organic solvent, followed byaddition of the appropriate acid and subsequent evaporation,precipitation or crystallization.

The invention will be illustrated, but not limited, by reference to thespecific embodiments described in the following schemes and examples.Unless otherwise indicated in the schemes, the variables have the samemeaning as described above. Unless otherwise specified, all startingmaterials are obtained from commercially suppliers and used withoutfurther purifications. Unless otherwise specified, all temperatures areexpressed in ° C. and all reactions are conducted at room temperature.Compounds were purified by either silica chromatography or preparativeHPLC.

The present invention also relates to processes for manufacturing thecompounds of Formula (I), Formula (II) and Formula (III) according tothe hereinafter described schemes and working examples.

In particular, the present invention relates to a process for themanufacture of compounds of Formula (I), wherein X is N and Y is NH, andall other substituents have the meaning as defined for Formula (I) inClaim 1, wherein a carboxylic acid ester of Formula (IV)

is reacted with a compound of Formula (V)

to yield a compound of Formula (VI)

which is finally converted into the carboxylic amide of Formula (I)

General Synthetic Procedures

Arylaldehyde 1a was reacted with nitro methane under basic conditions toprovide the hydroxyl derivative 1b, which was converted to the alkene 1cunder acetic anhydride promoted elimination conditions. Cyclization of1c with N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine gavepyrrolidine derivative 1d. Reduction of the nitro group in 1d usingRaney nickel as a catalyst, followed by the Teoc protection of theresulting amino moiety withN-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide gave 1f. The N-benzylgroup of 1f was removed under hydrogenation conditions, and protectedwith di-tert-butyl dicarbonate to provide 1h. The Teoc protected primaryamine in 1h was released upon treatment with tetra-n-butylammoniumfluoride to provide 1i.

2a was coupled withN-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine in the presenceof trifluoroacetic acid to provide pyrrolidine derivative 2b. The benzylprotecting group in 2b was removed using ACE-CI to afford free secondaryamine 2c. Treatment of 2c with di-tert-butyl dicarbonate, followed byindium promoted reduction of the nitro moiety gave compound 2e.

3a was coupled with 3-amino-4-aryl pyrrolidine to provide 3b. The methylester in 3b was converted to amide 3c by reacting with ammonia inmethanol. Treatment of 3c with HCl in dioxane removed the Boc protectinggroup to give 3d.

The pyrrolidine derivative 4a was treated with formaldehyde and formicacid to provide the N-methylpyrrolidine 4b. The Teoc protected primaryamine in 4b was release upon treatment with tetra-n-butylammoniumfluoride to provide 4c.

The 3-amino-4-aryl pyrrolidine was reacted with4-chloroquinoline-8-carbonitrile 5a under basic conditions to generate5b, which was hydrolyzed to give amide 5c. Subsequent protecting groupremoval provided 5d.

6a was protected as the benzyl carbamate to provide 6b. Subsequent esterhydrolysis and amide coupling provide 6d. Cbz removal via hydrogenationand reaction with methyl 4-chloroquinazoline-8-carboxylate delivered 6e.Conversion of the ester to the amide and protecting group removalprovided 6h.

Methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate (7a) wasneutralized with potassium carbonate to afford 7b, which upon reactingwith aryl magnesium bromide provided 7c as a mixture of cis and transisomers. Sodium methoxide promoted epimerization led to the exclusiveformation of the thermodynamically more stable trans-7d. The methylgroup was removed by ACE-CI, followed by treatment with methanol underrefluxing conditions to provide 7e. Protection of the amine withdi-tert-butyl dicarbonate, followed by ester hydrolysis gave acid 7g.Curtius rearrangement of 7g using diphenyl phosphorazidate (DPPA),followed by quenching the reaction with water provided 7i.

8a was coupled with 3-amino-4-aryl piperidine to generate 8b. Methylester aminolysis with ammonia in methanol, followed by the aminedeprotection provided 8d.

Addition of grignar reagent 9b to methyl1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate gave 9c as a cis andtrans mixture. Sodium methoxide promoted epimerization led to theexclusive formation of the thermodynamically more stable trans-9d. Themethyl group was removed by using ACE-CI, followed by treatment withmethanol under refluxing conditions to provide 9e. Protection of thesecondary amine as a benzyl carbamate, followed by ester hydrolysis gave9h. Curtius rearrangement of 9h using diphenyl phosphorazidate (DPPA),followed by quenching the reaction with t-butanol provided Boc protectedpiperidine 9j. Boc removal under acidic conditions provided 9k, whichwas coupled with methyl 4-chloroquinazoline-8-carboxylate to give 9l.Aminolysis of the methyl ester with ammonia in methanol, followed by theCbz removal provided desired 9n.

10a was treated with formaldehyde and formic acid to provide N-methyl10b.

As in Scheme 5, 5a was combined with 3-amino-4-aryl piperidinederivative to provide 11b. Nitrile hydrolysis and Boc removal provided11d.

12a was coupling with Aryl boronic acid, palladium acetate as catalyst,s-phos as ligand in basic condition to provide 12b, and Boc removalprovided 12c.

Analytical Methodology Analytical LC/MS was Performed Using theFollowing Three Methods: Method A:

A Discovery C¹⁸, 5 μm, 3×30 mm column was used at a flow rate of 400μL/min, sample loop 5 μL, mobile phase: (A) water with 0.1% formic acid,mobile phase, (B) methanol with 0.1% formic acid; retention times aregiven in minutes. Method details: (I) runs on a Quaternary Pump G1311A(Agilent) with UV/VIS diode array detector G1315B (Agilent) and FinniganLCQ Duo MS detector in ESI+modus with UV-detection at 254 and 280 nmwith a gradient of 15-95% (B) in a 3.2 min linear gradient (II) hold for1.4 min at 95% (B) (III) decrease from 95-15% (B) in a 0.1 min lineargradient (IV) hold for 2.3 min at 15% (B).

Method B:

A Waters Symmetry C¹⁸, 3.5 μm, 4.6×75 mm column at a flow rate of 1mL/min, sample loop 10 μL, mobile phase (A) is water with 0.05% TFA,mobile phase (B) is ACN with 0.05% TFA; retention times are given inminutes. Methods details: (I) runs on a Binary Pump G1312A (Agilent)with UV/Vis diode array detector G1315B (Agilent) and Agilent G1956B(SL) MS detector in ESI+mode with UV-detection at 254 and 280 nm with agradient of 20-85% (B) in a 10 min linear gradient (II) hold for 1 minat 85% (B) (III) decrease from 20-85% (B) in a 0.2 min linear gradient(IV) hold for 3.8 min at 20% (B).

Method C:

Gradient: 4.2 min/Flow: 2 ml/min 99:01-0:100 Water+0.1% (Vol.) TFA;Acetonitril+0.1% (Vol.) TFA; 0.0 to 0.2 min: 99:01; 0.2 to 3.8 min:99:01→0:100; 3.8 to 4.2 min: 0:100; Column: Chromolith PerformanceRP18e; 100 mm long, 3 mm diameter; Wavelength: 220 nm.

Analytical Chiral HPLC

Analytical chiral HPLC was performed using a ChiralPak AD-H column(250×4.6 mm) from Daicel Chemical Industries, Ltd. on an Agilent 1100Series system. The method used a 5.0 μL injection volume, with a flowrate of 1 mL/min of 100% methanol for 15 min at 25° C., and UV-detectionat 254 and 280 nm.

Preparative HPLC

Preparative HPLC was performed using either a Waters Atlantis dC₁₈ OBD™10 μM (30×250 mm) column or a Waters Sunfire Prep C₁₈ OBD 10 μM (30×250mm) column. The columns were used at a flow rate of 60 mL/min on aWaters Prep LC 4000 System equipped with a sample loop (10 mL) and anISCO UA-6 UV/Vis detector. The mobile phase was drawn from two solventreservoirs containing (A) water and (B) HPLC-grade acetonitrile. Atypical preparative run used a linear gradient (e.g., 0-60% solvent Bover 60 min).

Examples

The working examples presented below are intended to illustrateparticular embodiments of the invention, and are not intended to limitthe scope of the specification or the claims in any way.

Chemical Synthesis

In this section experimental details are provided for a number ofExample compounds according to Formula (I), and synthesis intermediatesthereof.

Synthesis Intermediates

tert-Butyl 3-amino-4-(3-fluorophenyl)pyrrolidine-1-carboxylate (1)1-(3-Fluoro-phenyl)-2-nitro-ethanol

A solution of 3-fluorobenzaldehyde (21.37 ml; 201.43 mmol; 1.00 eq.) andnitromethane (13.06 ml; 241.71 mmol; 1.20 eq.) in MeOH (40 ml) wascooled to −10° C. A solution of NaOH (8.46 g; 211.50 mmol; 1.05 eq.) inH₂O (20 ml) was added over 10 min, keeping the temperature below −5° C.The reaction mixture was stirred at −5° C. for 15 min, during which thereaction solution solidified as a white solid. The reaction mixture waswarmed to 0° C., and diluted with H₂O (150 ml). Upon dissolution of allof the solids, HCl (4M, 100 ml) was added. The reaction mixture wasextracted with DCM (300 ml×2). The combined extracts were washed withbrine and concentrated to provide the desired intermediate (34.8 g,yield 93%).

1-Fluoro-3-((E)-2-nitro-vinyl)-benzene

N,N-Dimethylpyridin-4-amine (2.30 g; 18.80 mmol) was added to a solutionof 1-(3-fluorophenyl)-2-nitroethanol (34.80 g; 187.95 mmol) in aceticanhydride (35.53 ml; 375.90 mmol) at 0° C., and stirred at RT for 72 h.The reaction mixture was quenched by pouring into a vigorously stirredsatd. NaHCO₃ solution (400 mL). The desired intermediate was extractedwith EtOAc (3×100 mL). The organic extracts were washed with satd.NaHCO₃, brine, dried over MgSO4, filtered, and concentrated to providethe desired intermediate (26.0 g, yield 83%).

Trans-1-Benzyl-3-(3-fluoro-phenyl)-4-nitro-pyrrolidine

N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine was added to asolution of 1-fluoro-3-[(E)-2-nitrovinyl]benzene (6.00 g; 35.90 mmol) inDCM (50 ml). The reaction solution was cooled to 0° C., TFA (0.30 ml;3.95 mmol) was added drop wise, and stirred overnight at RT. Thereaction solution was washed with H₂O and brine, dried over MgSO4,filtered, and concentrated. The crude material was purified via Biotage(340 g column) eluting with 5% EtOAc in hexane to provide the desiredproduct (5.5 g, yield 51%).

(Trans-1-Benzyl-4-(3-fluoro-phenyl)-pyrrolidin-3-ylamine

Trans-1-benzyl-3-(3-fluorophenyl)-4-nitropyrrolidine (5.50 g; 18.31mmol) was dissolved in MeOH (300 mL). NH₃ (30 ml, 2.0M in MeOH) wasadded, and the solution was passed through the H cube (flow 1.5 min/min,full H₂, at 50° C.). The reaction solution was concentrated to providethe desired intermediate (4.6 g, yield 92%). LC-MS (M+H=271, obsd=271).

[Trans-1-Benzyl-4-(3-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acidpropyl ester

1-({[2-(Trimethylsilyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione (4.5 g;17.37 mmol) was added to a solution oftrans-1-benzyl-4-(3-fluorophenyl)pyrrolidin-3-amine (4.5 g; 16.87 mmol)and DIEA (4.5 ml; 25.30 mmol) in DCM (50 ml) at 0° C., warmed to RT, andstirred for 1 hr at RT. The reaction solution was washed with brine,dried over MgSO₄, filtered, and concentrated. The crude material waspurified was purified by Biotage eluting with a gradient of 30 to 60%EtOAc in hexane to provide the desired intermediate (6.0 g, yield 99%).LC-MS (M+H=415, obsd=415).

[Trans-4-(3-Fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid propyl ester

AcOH (2 mL) was added to a solution of 2-(trimethylsilyl)ethyl[trans-benzyl-4-(3-fluorophenyl)pyrrolidin-3-yl]carbamate (2.50 g; 6.03mmol) in EtOH (150 ml). Pd/C (1.25 g, wet, 10% Pd) was then added, andthe reaction mixture was put on a par shaker (60 Psi), and reacted for 2h. The reaction mixture was filtered, and the filtrate was concentratedto provide the desired product (1.96 g, quantitative yield). LC-MS(M+H=325, obsd=325).

Trans-3-(3-Fluoro-phenyl)-4-propoxycarbonylamino-pyrrolidine-1-carboxylicacid tert-butyl ester

Di-tert-butyl dicarbonate (1.27 g; 5.82 mmol) was added to a solution of2-(trimethylsilyl)ethyl[trans-4-(3-fluorophenyl)pyrrolidin-3-yl]carbamate (1.80 g; 5.55 mmol)and DIEA (2.2 ml; 12.26 mmol) in DCM (100 ml), and stirred overnight atRT. The reaction mixture was concentrated, and the crude product waspurified via Biotage eluting with a gradient of 20 to 60% EtOAc inhexanes to provide the desired intermediate (2.0 g, yield 85%). LC-MS(M+H=425, obsd=425).

1-Benzyl-4-(3-fluorophenyl)pyrrolidin-3-amine

Tert-butylTrans-3-(3-fluorophenyl)-4-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)-pyrrolidine-1-carboxylate(2.4 g; 5.76 mmol) and N,N,N-tributylbutan-1-aminium fluoride (20.00 ml;1.00 M; 20.00 mmol) was dissolved in MeOH, and stirred overnight at RT.The crude product was purified via Biotage eluting with a gradient of 5to 10% MeOH in DCM to provide 1 (1.61 g, yield 79%). LC-MS (M+H=281,obsd=281). ¹HNMR (DMSO-d6) δ 1.39 (s, 9H), 1.55 (s, 1H), 2.90-2.99 (m,2H), 3.24-3.26 (m, 1H), 3.33-3.37 (m, 1H), 3.55-3.57 (m, 1H), 3.60-3.68(m, 1H), 3.70-3.72 (m, 1H), 7.05-7.06 (m, 1H), 7.13-7.15 (m, 2H),7.35-7.36 (m, 1H).

trans racemic4-((4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(2)

IC₅₀p70S6K [uM]: 0.003

Methyl4-((1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxylate

Methyl 4-chloroquinazoline-8-carboxylate (80.00 mg; 0.36 mmol), DIEA(0.13 ml; 0.72 mmol), and racemic trans tert-butyl3-amino-4-(3-fluorophenyl)pyrrolidine-1-carboxylate (109 mg; 0.37 mmol)were dissolved in CH₃CN, and stirred overnight at RT. The reactionmixture was concentrated, redissolved in methanolic NH₃ (1.50 ml; 7.00M; 10.50 mmol), and stirred for 72 h at RT. The reaction mixture wasconcentrated to provide the desired intermediate. LC-MS (M+H=452,obsd=452).

4-((4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide

HCl in dioxane (1.5 ml; 4.00 M; 6.00 mmol) was added to a solution oftert-butyl3-{[8-(aminocarbonyl)quinazolin-4-yl]amino}-4-(3-fluorophenyl)-pyrrolidine-1-carboxylate(162 mg; 0.36 mmol) in MeOH (1.5 ml), and stirred overnight at RT. Theresulting precipitate was filtered washed with MeOH and ether, and driedunder vacuum to provide 2 (67 mg, 44% yield) as an HCl salt. LC-MS(M+H=352, obsd=352). ¹HNMR (DMSO-d6) δ 2.86-2.88 (m, 2H), 3.39-3.42 (m,2H), 4.09-4.11 (d, 1H), 4.81-4.84 (m, 1H), 7.05 (t, 1H), 7.17 (t, 1H),7.32 (q 1H), 7.62 (t, 1H), 7.81 (d, 1H), 8.52-8.65 (m, 4H), 10.33 (d,1H).

trans racemic4-((4-phenylpyrrolidin-3-yl)-amino)quinazoline-8-carboxamide (3)

IC₅₀p70S6K [uM]: 0.0049

The compound was synthesized according to the procedure described forthe preparation of example 2 using trans racemic tert-butyl3-amino-4-phenylpyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=334, obsd=334). ¹HNMR(DMSO-d6) δ 3.42-3.45 (m, 2H), 3.78-3.86 (m, 2H), 4.04-4.08 (m, 1H),5.23 (t, 1H), 7.26-7.32 (m, 1H), 7.32-7.34 (m, 2H), 7.48-7.05 (m, 2H),7.84 (t, 1H), 8.15 (s, 1H), 8.54 (d, 1H), 8.77 (s, 1H), 8.98 (s, 1H),9.80 (s, 2H).

4-((4-(2-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(4)

IC₅₀p70S6K [uM]: 0.0035

The compound was synthesized according to the procedure described forthe preparation of example 2 using trans racemic tert-butyl3-amino-4-(2-fluorophenyl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=352, obsd=352).

4-((4-(4-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(5)

IC₅₀p70S6K [uM]: 0.0026

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(4-fluorophenyl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=352, obsd=352).

4-((4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(6)

IC₅₀p70S6K [uM]: 0.002

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(4-methoxyphenyl)-pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=364, obsd=364).

4-((4-(3-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(7)

IC₅₀p70S6K [uM]: 0.0026

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-methoxyphenyl)-pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate.

LC-MS (M+H=364, obsd=364).

4-((4-(2-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(8)

IC₅₀p70S6K [uM]: 0.018

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(2-methoxyphenyl)-pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate.

LC-MS (M+H=364, obsd=364).

trans, racemic4-((4-(3-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(9)

IC₅₀p70S6K [uM]: 0.0013

The compound was synthesized according to the procedure described forthe preparation of example 2 using trans, racemic tert-butyl3-amino-4-(3-chlorophenyl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=368, obsd=368/370).

trans, racemic4-((4-(2-chloro-6-fluorophenyl)pyrrolidin-3-yl)amino)-quinazoline-8-carboxamide(10)

IC₅₀p70S6K [uM]: 0.007

The compound was synthesized according to the procedure described forthe preparation of example 2 using trans, racemic tert-butyl3-amino-4-(2-chloro-6-fluorophenyl)pyrrolidine-1-carboxylate and methyl4-chloro-quinazoline-8-carboxylate. LC-MS (M+H=386, obsd=386/388).

trans, racemic4-((4-(3-bromophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(11) racemic 1-benzyl-3-(3-bromophenyl)-4-nitropyrrolidine

N-Benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (5.05 g; 20.00mmol) was added to a solution of 1-bromo-3-[(E)-2-nitrovinyl]benzene(3.80 g; 16.66 mmol) in DCM (50 ml), and cooled to 0° C. TFA (0.14 ml;1.83 mmol) was added, and the reaction was stirred overnight at RT. Thereaction mixture was washed with water and brine, dried over MgSO₄,filtered and concentrated. The crude product was purified via Biotage(100 g column) eluting with 5% EtOAc in hexane to provide the desiredintermediate. LC-MS (M+H=362, obsd=360/362).

tert-butyl 3-(3-bromophenyl)-4-nitropyrrolidine-1-carboxylate

Cs₂CO₃ (0.47 g; 1.45 mmol) and 1-chloroethyl chloridocarbonate (2.00 ml;18.33 mmol) were added to a solution of(3R,4S)-1-benzyl-3-(3-bromophenyl)-4-nitropyrrolidine (2.62 g; 7.25mmol) in DCE (100 ml), and stirred at 80° C. for 2 h. The reactionmixture was filtered, the filtrate was concentrated, and the residue wasredissolved in MeOH (100 ml). The reaction solution was stirred at 60°C. for 2 h, and concentrated to provide a yellow oil.

The above intermediate, DIEA (3.91 ml; 21.76 mmol), and di-tert-butyldicarbonate (1.90 g; 8.70 mmol) were dissolved in DCM (100 ml), andstirred overnight at RT. The reaction solution was washed with brine,dried over MgSO₄, filtered and concentrated. The crude product waspurified via Biotage eluting with a gradient of 10 to 20% EtOAc inhexanes to provide the desired intermediate (1.11 g, 41% yield). LC-MS(M+H=272, obsd=270/272).

tert-butyl 3-amino-4-(3-bromophenyl)pyrrolidine-1-carboxylate

tert-Butyl 3-(3-bromophenyl)-4-nitropyrrolidine-1-carboxylate (1.10 g;2.96 mmol), indium (3.40 g; 29.63 mmol), and ammonium chloride (1.59 g;29.63 mmol) were dissolved in H₂O (70 ml) and EtOH (70 ml) and refluxedfor 4 h. The reaction mixture was filtered, and the filtrate wasconcentrated. The resulting residue was diluted with DCM, washed withbrine, dried over MgSO₄, filtered, and concentrated. LC-MS (M+H=342,obsd=340/342).

The compound was synthesized according to the procedure described forthe preparation of example 2 using the above intermediate, trans racemictert-butyl 3-amino-4-(3-bromophenyl)pyrrolidine-1-carboxylate, andmethyl 4-chloroquinazoline-8-carboxylate. LC-MS (M+H=413, obsd=413).

trans, racemic4-((4-(3-fluorophenyl)-1-methylpyrrolidin-3-yl)amino)quinazoline-8-carboxamide(12)

IC₅₀p70S6K [uM]: 0.023

2-(trimethylsilyl)ethyl(4-(3-fluorophenyl)-1-methylpyrrolidin-3-yl)carbamate

2-(Trimethylsilyl)ethyl [4-(3-fluorophenyl)pyrrolidin-3-yl]carbamate(300.00 mg; 0.92 mmol), formic acid (0.10 ml; 2.31 mmol), andformaldehyde (0.09 ml; 1.11 mmol) were dissolved in EtOH, and stirredfor 3 h at 80° C. The reaction solution was concentrated to provide thedesired intermediate. LC-MS (M+H=339, obsd=339).

4-(3-fluorophenyl)-1-methylpyrrolidin-3-amine

2-(trimethylsilyl)ethyl[4-(3-fluorophenyl)-1-methylpyrrolidin-3-yl]carbamate (300.00 mg; 0.89mmol), and N,N,N-tributylbutan-1-aminium fluoride (5.00 ml; 1.00 M; 5.00mmol; 5.64 eq.) were dissolved in MeOH, and stirred at RT for 3 h. Thecrude product was purified via prep HPLC to provide the desiredintermediate (150 mg, 55% yield). LC-MS (M+H=195, obsd=195).

The compound was synthesized according to the procedure described forthe preparation of example 2 using the intermediate above, trans,racemic 4-(3-fluorophenyl)-1-methylpyrrolidin-3-amine, and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=366, obsd=366).

trans, racemic4-((−4-(naphthalen-2-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(13)

The compound was synthesized according to the procedure described forthe preparation of example 2 using trans, racemic, tert-butyl3-amino-4-(naphthalen-2-yl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=384, obsd=384).

trans, racemic4-((4-(naphthalen-1-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(14)

The compound was synthesized according to the procedure described forthe preparation of example 2 using trans, racemic tert-butyl3-amino-4-(naphthalen-1-yl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=384, obsd=384).

6-methyl-4-((4-phenylpyrrolidin-3-yl)amino)quinazoline-8-carboxamide(15)

IC₅₀p70S6K [nM]: 349

The compound was synthesized according to the procedure described forthe preparation of example 2 using trans, racemic tert-butyl3-amino-4-phenylpyrrolidine-1-carboxylate and4-chloro-6-methylquinazoline-8-carboxamide. LC-MS (M+H=348, obsd=348).

2-methyl-4-((4-phenylpyrrolidin-3-yl)amino)quinazoline-8-carboxamide(16)

IC₅₀p70S6K [uM]: 0.006

The compound was synthesized according to the procedure described forthe preparation of example 2 using trans, racemic tert-butyl3-amino-4-phenylpyrrolidine-1-carboxylate and4-chloro-2-methylquinazoline-8-carboxamide. LC-MS (M+H=348, obsd=348).

4-((4-(4-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide(17)

IC₅₀p70S6K [uM]: 0.0024

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(4-fluorophenyl)pyrrolidine-1-carboxylate and4-chloro-2-methylquinazoline-8-carboxamide.

LC-MS (M+H=366, obsd=366).

4-((4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide(18)

IC₅₀p70S6K [uM]: 0.0018

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(4-methoxyphenyl)pyrrolidine-1-carboxylate and4-chloro-2-methylquinazoline-8-carboxamide.

LC-MS (M+H=378, obsd=378).

4-((4-(4-fluorophenyl)-1-methylpyrrolidin-3-yl)amino)quinoline-8-carboxamide(19)

IC₅₀p70S6K [uM]: 0.5

3-(8-Cyano-quinolin-4-ylamino)-4-(4-fluoro-phenyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

4-Chloroquinoline-8-carbonitrile (200 mg; 1.06 mmol), tert-butyl3-amino-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (386 mg; 1.38 mmol),and K₂CO₃ (732 mg; 5.30 mmol) were dissolved in DMF (7 mL), and stirredat 80-100° C. for 7 days. The reaction material was purified directlyvia HPLC to provide the desired intermediate (50 mgs). LC-MS (M+H=433,obsd=433). ¹H NMR (400 MHz, DMSO-D₆): 3.3890 (m, 2H), 3.8405 (m, 2H),4.1107 (m, 1H), 4.9560 (m, 1H), 6.7967 (m, 1H), 7.1788 (t, 2H), 7.5442(m, 2H), 7.8425 (m, 1H), 8.2160 (s, 1H), 8.5086 (m, 2H), 8.7933 (m, 1H),9.1442 (d, 1H), 9.8576 (m, 1H), 9.9730 (m, 1H), 10.0985 (m, 1H).

tert-butyl3-((8-cyanoquinolin-4-yl)amino)-4-(4-fluorophenyl)pyrrolidine-1-carboxylate

tert-Butyl3-[(8-cyanoquinolin-4-yl)amino]-4-(4-fluorophenyl)pyrrolidine-1-carboxylate(20 mg; 0.05 mmol) and K₂CO₃ (51 mg; 0.37 mmol) were dissolved in DMSO(5 mL). H₂O₂ (179 mg; 1.85 mmol) was added drop wise, and the reactionmixture was stirred overnight at 50° C. The crude was purified via prepHPLC to provide the desired intermediate (35 mg). LC-MS (M+H=451,obsd=451).

4-((4-(4-fluorophenyl)-1-methylpyrrolidin-3-yl)amino)quinoline-8-carboxamide

tert-Butyl3-{[8-(aminocarbonyl)quinolin-4-yl]amino}-4-(4-fluorophenyl)pyrrolidine-1-carboxylate(25 mg; 0.02 mmol) was dissolved in HCl in dioxane (0.06 ml; 4.00 M;0.22 mmol), and stirred for 30 minutes. The resulting precipitate wasfiltered, washed with ether and then dried under vacuum to provide 14(21 mg). LC-MS (M+H=351, obsd=351). ¹H NMR (400 MHz, DMSO-D₆): 3.3890(m, 2H), 3.8405 (m, 2H), 4.1107 (m, 1H), 4.9560 (m, 1H), 6.7967 (m, 1H),7.1788 (t, 2H), 7.5442 (m, 2H), 7.8425 (m, 1H), 8.2160 (s, 1H), 8.5086(m, 2H), 8.7933 (m, 1H), 9.1442 (d, 1H), 9.8576 (m, 1H), 9.9730 (m, 1H),10.0985 (m, 1H).

4-((4-phenylpyrrolidin-3-yl)amino)quinoline-8-carboxamide (20)

The compound was synthesized according to the procedure described forthe preparation of example 19 using tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate and methyl 4-chloroquinoline-8-carbonitrile.LC-MS (M+H=333, obsd=333).

4-((4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide (21)

IC₅₀p70S6K [uM]: 0.013

The compound was synthesized according to the procedure described forthe preparation of example 19 using tert-butyl3-amino-4-(3-fluorophenyl)pyrrolidine-1-carboxylate and4-chloroquinoline-8-carbonitrile. LC-MS (M+H=351, obsd=351).

4-((4-(2-fluorophenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide (22)

IC₅₀p70S6K [uM]: 0.0094

The compound was synthesized according to the procedure described forthe preparation of example 19 using tert-butyl3-amino-4-(2-fluorophenyl)pyrrolidine-1-carboxylate and4-chloroquinoline-8-carbonitrile. LC-MS (M+H=351, obsd=351).

4-((4-(2-methoxyphenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide(23)

IC₅₀p70S6K [uM]: 0.046

The compound was synthesized according to the procedure described forthe preparation of example 19 using tert-butyl3-amino-4-(2-methoxyphenyl)pyrrolidine-1-carboxylate and methyl4-chloroquinoline-8-carbonitrile. LC-MS (M+H=363, obsd=363).

4-((4-(3-methoxyphenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide(24)

The compound was synthesized according to the procedure described forthe preparation of example 19 using tert-butyl3-amino-4-(3-methoxyphenyl)pyrrolidine-1-carboxylate and4-chloroquinoline-8-carbonitrile. LC-MS (M+H=363, obsd=363).

4-((4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide(25)

The compound was synthesized according to the procedure described forthe preparation of example 19 using tert-butyl3-amino-4-(4-methoxyphenyl)pyrrolidine-1-carboxylate and4-chloroquinoline-8-carbonitrile. LC-MS (M+H=363, obsd=363).

trans-4-(4-Phenylcarbamoyl-pyrrolidin-3-ylamino)-quinazoline-8-carboxylicacid amide (26)

IC₅₀p70S6K [uM]: 0.022 F

(trans)-4-Benzyloxycarbonylamino-pyrrolidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester

1-tert-Butyl 3-ethyl (trans)-4-aminopyrrolidine-1,3-dicarboxylatehydrochloride (500 mg; 1.70 mmol) and DIEA (886 μl; 5.09 mmol) weredissolved in DMF (17 ml). The solution was cooled to 0° C., benzylchloroformate (358; 2.54 mmol) was added drop wise via syringe, and thereaction was stirred overnight at RT. The reaction was diluted with H₂Oand extracted with EtOAc (3×10 mL). The organic extracts were dried,concentrated on SiO2, and purified via Biotage (10 g column) using 1%MeOH in DCM to provide the desired intermediate (600 mg, 43% yield.LC-MS: (M-Boc)+H=293, obsd.=293).

(trans)-4-Benzyloxycarbonylamino-pyrrolidine-1,3-dicarboxylic acid1-tert-butyl ester)

(trans)-4-Benzyloxycarbonylamino-pyrrolidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester (284 mg; 0.72 mmol) was dissolved inTHF (5 ml) and then treated with LiOH (0.72 ml; 3.00 M; 2.17 mmol). Thereaction was stirred at RT for 2 h. The reaction was diluted with H₂Oand washed with EtOAc. The aqueous layer was acidified with solid KHSO₄and extracted with EtOAc (3×). The organic extracts were washed with H₂Oand brine, dried over Na₂SO₄, filtered and concentrated to provide thedesired intermediate (quantitative yield) as a white solid. ¹H NMR (inDMSO): 1.39 (s, 9H), 2.93 (m, 1H), 3.07 (m, 1H), 3.51-3.55 (m, 3H), 4.23(m, 1H), 5.03 (s, 2H), 7.32-7.38 (m, 5H), 7.70 (m, 1H), 12.5 (s, 1H).LC-MS: (M-Boc)+H=265, obsd.=265.

(trans)-3-Benzyloxycarbonylamino-4-phenylcarbamoyl-pyrrolidine-1-carboxylicacid tert-butyl ester

(trans)-4-Benzyloxycarbonylamino-pyrrolidine-1,3-dicarboxylic acid1-tert-butyl ester (270 mg; 0.74 mmol) and 1-hydroxybenzotriazole (105mg, 0.78 mmol) were dissolved into DMF (5 mL), and stirred for 5 minutesuntil solids dissolved entirely. Aniline (81 μl; 0.89 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (193 mg,1.01 mmol) were added, and the yellow solution was stirred for 90 min.at 50° C. The reaction was quenched with H₂O (40 mL) and MeOH (5 mL).The resulting precipitate was filtered to provide the desiredintermediate (293 mg, 90% yield). LC-MS: (M-Boc)+H=340, obsd.=340.

¹HNMR (in DMSO): 1.39 (s, 9H), 3.10 (m, 2H), 3.35 (m, 1H), 3.63-3.67 (m,2H), 4.27 (m, 1H), 5.01-5.04 (m, 2H), 7.04-7.07 (t, 1H), 7.22-7.32 (m,7H), 7.56-7.58 (d, 2H), 7.72 (d, 1H), 10.03 (s, 1H).

4-((trans)-1-tert-Butoxycarbonyl-4-phenylcarbamoyl-pyrrolidin-3-ylamino)-quinazoline-8-carboxylicacid methyl ester

(trans)-3-Benzyloxycarbonylamino-4-phenylcarbamoyl-pyrrolidine-1-carboxylicacid tert-butyl ester (286 mg; 0.65 mmol) was dissolved in MeOH (15 ml).10% Pd—C (143 mg) was added, and the reaction mixture was stirred atroom temperature under H₂ atm (balloon) overnight. The reaction wasfiltered through celite, and concentrated. The crude material fromabove, methyl 4-chloroquinazoline-8-carboxylate (138 mg; 0.65 mmol), andDIEA (325; 1.87 mmol) were dissolved in THF (5 ml), and stirred at 60°C. for 4 days. The reaction mixture was concentrated and purified viaprep HPLC to afford the desired intermediate (300 mg, 80% yield over 2steps) as a white solid. LC-MS: M+H=492, obsd.=492. ¹HNMR (in DMSO):1.43 (s, 9H), 3.43-3.51 (m, 3H), 3.87-3.91 (m, 2H), 5.17 (d, 1H),7.03-7.06 (t, 1H), 7.28-7.30 (t, 2H), 7.53-7.55 (d, 2H), 7.83 (t, 1H),8.08 (s, 1H), 8.55-8.57 (d, 1H), 8.69 (d, 1H), 8.76 (s, 1H), 9.00-9.90(s, 2H), 10.1 (s, 1H).

4-((trans)-4-Phenylcarbamoyl-pyrrolidin-3-ylamino)-quinazoline-8-carboxylicacid amide

4-((trans)-1-tert-Butoxycarbonyl-4-phenylcarbamoyl-pyrrolidin-3-ylamino)-quinazoline-8-carboxylicacid methyl ester (290 mg; 0.48 mmol) was dissolved in iPrOH (2 ml),DMSO (4 ml), and ammonium hydroxide (4 ml), and stirred overnight at 70°C. The reaction mixture was partially concentrated, diluted with H₂O,and extracted with EtOAc (3×). The organic extracts were washed with 1NNaOH and brine, dried over Na₂SO₄), filtered, and concentrated. Thecrude material was purified via prep HPLC. The purified material fromabove (153 mg; 0.26 mmol) was dissolved in dioxane (3 mL) and 4.0M HClin dioxane (3 mL), and stirred for 90 min. at RT. The reaction mixturewas concentrated and washed with MeOH (2×) to provide 26 (114 mg, 98%yield) as a white solid. LC-MS: M+H=377, obsd.=377. ¹HNMR (in DMSO):3.39-3.87 (m, 5H), 5.21 (t, 1H), 7.05-7.08 (t, 1H), 7.29-7.32 (t, 2H),7.58-7.63 (d, 2H), 7.84 (t, 1H), 8.10 (s, 1H), 8.58 (d, 1H), 8.77 (s,1H), 9.07 (s, 1H), 9.54 (s, 1H), 9.66 (s, 1H), 10.6 (s, 1H).

trans, racemic4-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide (27)

IC₅₀p70S6K [uM]: 0.0063

tert-Butyl3-((8-carbamoylquinazolin-4-yl)amino)-4-phenylpiperidine-1-carboxylate

Methyl 4-chloroquinazoline-8-carboxylate (750 mg; 3.37 mmol), DIEA (1.21ml; 6.74 mmol), and trans, racemic tert-butyl3-amino-4-phenylpiperidine-1-carboxylate (959.00 mg; 3.47 mmol) weredissolved in CH₃CN (5 mL), and stirred at 45° C. for 72 h. The reactionmixture was concentrated.

The crude residue from above was dissolved in methanolic ammonia (4.8ml; 7.00 M; 33.69 mmol) and stirred overnight at 60 C. The reactionmixture was concentrated, redissolved in HCl in MeOH (5.00 ml; 4.00 M;20.00 mmol), and stirred overnight at RT. The reaction mixture wasfiltered, and the precipitate was washed with MeOH and ether to provide27 (1000 mg, 81% yield). LC-MS (M+H=421, obsd=348). ¹HNMR (DMSC-d6) δ1.69-1.70 (m, 1H), 1.79 (d, 1H), 2.50-2.51 (m, 1H), 3.00-3.03 (m, 2H),3.18 (d, 1H), 4.62-4.66 (m, 1H). 7.05 (t, 1H), 7.16 (t, 2H), 7.29 9t,2H), 7.54 (t, 1H), 7.78 (d, 1H), 8.15 (d, 1H), 8.30 (d, 1H), 8.47-8.499d, 2H).

racemic, trans4-((4-(3-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(28)

IC₅₀p70S6K [uM]: 0.0018

The compound was synthesized according to the procedure described forthe preparation of example 27 using racemic, trans tert-butyl3-amino-4-(3-fluorophenyl)piperidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=366, obsd=366).

cis, racemic 4-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide(29)

The compound was synthesized according to the procedure described forthe preparation of example 27 using cis, racemic tert-butyl3-amino-4-phenylpiperidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=348, obsd=348). ¹HNMR(DMSC-d6) δ 1.98-2.20 (d, 1H), 2.60-2.70 (m, 1H), 3.50-3.56 (m, 4H),5.34 (d, 1H), 6.91 (t, 1H), 7.14-7.21 (m, 3H), 7.76 (t, 1H), 7.98 (s,1H), 8.52-8.55 (m, 3H), 8.72 (d, 1H), 9.16 9d, 1H).

trans, racemic4-((4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(30)

IC₅₀p70S6K [uM]: 0.0021

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans, racemic tert-butyl3-amino-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=416, obsd=416).

trans, racemic4-((4-(m-tolyl)piperidin-3-yl)amino)quinazoline-8-carboxamide (31)

IC₅₀p70S6K [uM]: 0.0031

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans, racemic tert-butyl3-amino-4-(m-tolyl)piperidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=362, obsd=362).

trans, racemic4-((4-(4-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(32)

IC₅₀p70S6K [uM]: 0.0032

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans, racemic tert-butyl3-amino-4-(4-fluorophenyl)piperidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=366, obsd=366).

trans, racemic tert-butyl3-amino-4-(4-chlorophenyl)piperidine-1-carboxylate (33) Methyl1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate

K₂CO₃ (50 g; 361.78 mmol) was added to a solution of methyl1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate hydrobromide (50 g;211.77 mmol) in H₂O (50 ml) and DCM (250 ml), and stirred at RT for 30mins. The organic layer was separated, washed with brine, dried overMgSO₄, filtered and concentrated to provide the desired intermediate (34g, quantitative yield).

Methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate

Bromo(4-chlorophenyl)magnesium (47 ml; 1.00 M; 47.27 mmol) was added toa solution of methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate(5.24 g; 33.76 mmol) in ether (150 ml) at −10° C. over 45 min. Thereaction mixture was stirred for 20 min, and then quenched with satd.NH₄Cl. The organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated. The crude product was purified via Biotageeluting with a gradient of 20 to 60% EtOAc in hexane with 4% TEA toprovide the desired intermediate as a mixture of cis and trans isomers(2.8 g).

trans, racemic Methyl4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate

Sodium methoxide (4.3 g; 19.83 mmol) was added to a solution of methyl4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate (5.3 g; 19.83 mmol)in MeOH (100 ml), and stirred at 60° C. for 6 h. The reaction mixturewas concentrated, the residue was diluted with EtOAC (100 ml), washedwith satd. NH₄Cl and brine, dried over MgSO₄, filtered, and concentratedto provide the desired trans intermediate (4.9 g, 92% yield). ¹HNMR(DMSO-d6) δ 1.91 (m, 1H), 2.20-2.22 (m, 1H), 2.78 (s, 3H) 2.99-3.01 (m,1H0, 3.06-3.25 (m, 2H), 3.31-3.52 (m, 2H), 3.36 (s, 1H), 7.22 (d, 2H),7.43 (d, 2H).

trans, racemic 1-tert-Butyl 3-methyl4-(4-chlorophenyl)piperidine-1,3-dicarboxylate

Cs₂CO₃ (1.19 g; 3.65 mmol) was added to a solution of trans, racemicmethyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate (4.89 g;18.26 mmol) in DCE (100 ml). 1-chloroethyl chloridocarbonate (2.99 ml;27.39 mmol) was added drop wise, and the reaction mixture was stirred at80° C. for 1 h. The reaction was concentrated, the residue wasredissolved in MeOH (100 ml), and stirred at 60° C. for 2 h. Thereaction mixture was concentrated, and the residue was redissolved inDCM (100 ml). DIEA (9.84 ml; 54.79 mmol) and di-tert-butyl dicarbonate(4.78 g; 21.92 mmol) were added, and the reaction mixture was stirredovernight at RT. The reaction solution was washed with brine, dried overNa₂SO₄, filtered, and concentrated. The crude material was purified viaBiotage eluting with a gradient of 10 to 25% EtOAc in hexane to providethe desired intermediate (4.8 g, 74% yield). LC-MS (M+H=354, obsd=354).

trans, racemic1-(tert-butoxycarbonyl)-4-(4-chlorophenyl)piperidine-3-carboxylic acid

1-tert-Butyl 3-methyl 4-(4-chlorophenyl)piperidine-1,3-dicarboxylate(4.80 g; 13.57 mmol) and LiOH (0.97 g; 40.70 mmol) were dissolved in THF(20 ml) and H₂O (20 ml), and stirred overnight at 40° C. Acetic acid wasadded to adjust the pH to 5. The product was extracted with DCM, washedwith brine, dried over MgSO₄, filtered and concentrated to provide thedesired intermediate (3.66 g, 79% yield). MS [240, fragmentation, M+1minus C(O)—O-t-Bu].

trans, racemic tert-butyl3-amino-4-(4-chlorophenyl)piperidine-1-carboxylate

1-(tert-Butoxycarbonyl)-4-(4-chlorophenyl)piperidine-3-carboxylic acid(1.4 g; 4.12 mmol), diphenyl azidophosphate (1.10 ml; 4.94 mmol), andTEA (1.74 ml; 12.36 mmol) were dissolved in DCE (5 ml), and stirred atRT for 3 h. The reaction mixture was diluted with toluene, washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue wasredissolved in toluene (10 ml), and heated at reflux for 5 h. Thereaction mixture was cooled to room temperature, H₂O (445 mg; 24.72mmol) was added, and the reaction was reheated at reflux for 12 h. Thereaction mixture was concentrated, and the crude material was purifiedby Biotage eluting with a gradient of 20 to 60% EtOAc in hexane toprovide 33 (577 mg). LC-MS (M+H=311, obsd=255 and small 311).

racemic, trans Benzyl3-amino-4-(3-fluoro-4-methylphenyl)piperidine-1-carboxylate (34) Methyl4-(3-fluoro-4-methylphenyl)-1-methylpiperidine-3-carboxylate

A solution of 4-Bromo-2-fluoro-1-methylbenzene (3.70 g; 20 mmol) inether (25 mL) was added drop wise to a suspension of Mg (0.49 g; 20.75mmol) in ether (20 ml) over 20 min to maintain gentle reflux, and thereaction mixture was stirred at RT for 2 h. The reaction mixture wascooled to −10° C., and a solution of methyl1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate (1.90 g; 10 mmol) inether (20 ml) was added drop wise over 15 min, and the reaction mixturewas stirred for 1 h. The reaction mixture was quenched with satd.aqueous NH₄Cl (35 ml), and diluted with EtOAc (50 mL. The organic layerwas isolated, washed NH₄Cl and brine, dried over Na₂SO₄, filtered, andconcentrated. The crude material was purified by the Biotage elutingwith a gradient of 30 to 50% EtOAc in hexane with 4% TEA to provide thedesired product (2.0 g, 62% yield) as a mixture of cis and transisomers. LC-MS (M+H=311, obsd=266).

trans, racemic methyl4-(3-fluoro-4-methylphenyl)-1-methylpiperidine-3-carboxylate

NaOMe (1.6 g; 7.54 mmol) was added to a solution of methyl4-(3-fluoro-4-methylphenyl)-1-methylpiperidine-3-carboxylate (2.0 g;7.54 mmol) in MeOH (30 ml), and stirred for 4 h at 60° C. The reactionmixture was concentrated to provide the desired intermediate (1.64 g,82% yield).

trans, racemic 1-Benzyl 3-methyl4-(3-fluoro-4-methylphenyl)piperidine-1,3-dicarboxylate

Cs₂CO₃ (0.40 g; 1.23 mmol) was added to a solution of trans, racemicmethyl 4-(3-fluoro-4-methylphenyl)-1-methylpiperidine-3-carboxylate(1.64 g, 6.17 mmol) in DCE (100 ml). 1-chloroethyl chloridocarbonate(0.71 ml; 6.48 mmol) was added drop wise, and the reaction mixture wasstirred at 80° C. for 1 h. The reaction mixture was concentrated,redissolved in MeOH (100 ml), and stirred overnight at 60° C. Thereaction mixture was concentrated, the residue was dissolved in DCM (100ml), DIEA (2.22 ml; 12.34 mmol) and1-{[(benzyloxy)carbonyl]oxy}pyrrolidine-2,5-dione (1.61 g; 6.48 mmol)were added, and the reaction mixture was stirred at RT for 3 h. Thereaction solution was washed with brine, dried over Na₂SO₄, filtered,and concentrated. The crude material was purified via Biotage elutingwith 20% EtOAc in hexane) to provide the desired intermediate (1.2 g,50% yield, two steps). LC-MS (M+H=386, obsd=386).

trans, racemic,1-((Benzyloxy)carbonyl)-4-(3-fluoro-4-methylphenyl)piperidine-3-carboxylicacid

1-Benzyl 3-methyl4-(3-fluoro-4-methylphenyl)piperidine-1,3-dicarboxylate (1.20 g; 3.11mmol) and LiOH (0.22 g; 9.34 mmol) were dissolved in H₂O (5 ml) and THF(5 ml), and stirred overnight at 40° C. Acetic acid was added to adjustthe pH to 5. The product was extracted with DCM (50 ml×2), The combinedorganic extracts were dried over Na₂SO₄, filtered, and concentrated. Thecrude material was purified via Biotage eluting with 20 to 50% EtOAc inhexane) to provide the desired intermediate (0.8 g, 70% yield). LC-MS(M+H=372, obsd=372).

trans, racemic Benzyl3-amino-4-(3-fluoro-4-methylphenyl)piperidine-1-carboxylate

1-[(Benzyloxy)carbonyl]-4-(3-fluoro-4-methylphenyl)piperidine-3-carboxylicacid (457.00 mg; 1.23 mmol) and TEA (0.52 ml; 3.69 mmol) were dissolvedin DCE (5 ml). Diphenyl azidophosphate (0.33 ml; 1.48 mmol) was added,and the reaction solution was stirred at RT for 3 h. The reactionsolution was diluted with toluene, washed with NaHCO₃ and brine, driedover MgSO₄, filtered, and concentrated. The residue was redissolved intoluene (5 ml), and stirred at 110° C. for 4 h. 2-methylpropan-2-ol(0.33 ml; 3.69 mmol) was added, and the solution was stirred overnight.The reaction mixture was concentrated, the residue was redissolved inMeOH (3 ml), HCl in dioxane (3.00 ml; 4.00 M; 12.00 mmol) was added, andthe reaction mixture was stirred for 2 h at RT. The reaction mixture wasconcentrated, triturated with ether, and filtered to provide 34 (240 mg,47% yield). LC-MS (M+H=415, obsd=343). ¹HNMR (DMSC-d6) δ 1.68-1.73 (m,1H), 2.21 (s, 1H), 2.84-2.88 (m, 3H), 3.35-3.39 (m, 1H0<3.56 (3.63 (m,2H), 4.07 (d, 1H), 4.48 (d, 1H), 5.11 (s, 2H), 7.09 (d, 1H), 7.18-7.26(m, 2H). 7.39-7.41 (m, 5H), 7.98 (s, 2H).

trans, racemic Benzyl3-((8-carbamoylquinazolin-4-yl)amino)-4-(3-fluoro-4-methylphenyl)piperidine-1-carboxylate(35)

IC₅₀p70S6K [nM]: 1000

Methyl 4-chloroquinazoline-8-carboxylate (120 mg; 0.54 mmol), DIEA (0.39ml; 2.16 mmol), and trans, racemic benzyl3-amino-4-(3-fluoro-4-methylphenyl)piperidine-1-carboxylatedihydrochloride (230 mg; 0.56 mmol) were dissolved in CH₃CN, and stirredat 40° C. 72 h. The reaction mixture was concentrated, redissolved inmethanolic ammonia (0.77 ml; 7.00 M; 5.39 mmol), and stirred overnightat 45° C. The reaction mixture was concentrated, and the crude productwas purified via prep HPLC to provide 35 (150 mg, 54% yield). LC-MS(M+H=514, obsd=514).

racemic, trans4-((4-(3-fluoro-4-methylphenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(36)

Benzyl3-{[8-(aminocarbonyl)quinazolin-4-yl]amino}-4-(3-fluoro-4-methylphenyl)piperidine-1-carboxylate(23 mg; 0.04 mmol) was dissolved in EtOH (1.5 ml). Formic acid ammoniate(28 mg; 0.45 mmol) and Pd(OH)₂ (30 mg; 0.02 mmol; 50% wet) were added,and the reaction mixture was stirred at 60° C. for 20 min. The crudeproduct was purified directly via prep HPLC to provide 36. LC-MS(M+H=380, obsd=380). ¹HNMR (DMSO-d6) δ 2.09 (s, 3H), 2.21 (m, 1H),3.13-3.24 (m, 2H), 3.52-3.59 (d, 1H), 3.72-2.77 (d, 1H), 4.86-4.90 (m,2H), 5.20-5.25 (m, 1H), 7.01-7.07 (m, 3H), 7.68 (t, 1H), 8.26-8.29 (d,1H), 8.54-8.56 (d, 1H), 8.65 (s, 1H).

trans, racemic4-((4-(3-fluorophenyl)piperidin-3-yl)amino)-2-methylquinazoline-8-carboxamide(37)

IC₅₀p70S6K [nM]: 2.5

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans, racemic tert-butyl3-amino-4-(3-fluorophenyl)piperidine-1-carboxylate and4-chloro-2-methylquinazoline-8-carboxamide. LC-MS (M+H=380, obsd=380).

trans, racemic2-ethyl-4-((4-(3-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(38)

IC₅₀p70S6K [uM]: 0.0017

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans, racemic tert-butyl3-amino-4-(3-fluorophenyl)piperidine-1-carboxylate and4-chloro-2-ethylquinazoline-8-carboxamide. LC-MS (M+H=394, obsd=394).

trans, racemic2-ethyl-4-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide (39)

IC₅₀p70S6K [uM]: 0.0048

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans, racemic tert-butyl3-amino-4-phenylpiperidine-1-carboxylate and4-chloro-2-ethylquinazoline-8-carboxamide. LC-MS (M+H=376, obsd=376).

trans, racemic2-methyl-4-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide (40)

IC₅₀p70S6K [uM]: 0.0064

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans, racemic tert-butyl3-amino-4-phenylpiperidine-1-carboxylate and4-chloro-2-methylquinazoline-8-carboxamide.

LC-MS (M+H=362, obsd=362).

trans, racemic 4-((4-phenylpiperidin-3-yl)amino)quinoline-8-carboxamide(41)

The compound was synthesized according to the procedure described forthe preparation of example 19 using trans, racemic tert-butyl3-amino-4-phenylpiperidine-1-carboxylate and ethyl4-chloro-8-cyanoquinoline-3-carboxylate. LC-MS (M+H=347, obsd=347).

trans, racemic Ethyl8-carbamoyl-4-(4-phenylpiperidin-3-yl)amino)quinoline-3-carboxylate (42)

The compound was synthesized according to the procedure described forthe preparation of example 19 using trans, racemic tert-butyl3-amino-4-phenylpiperidine-1-carboxylate and4-chloro-8-cyanoquinoline-3-ethyl ester.

LC-MS (M+H=419, obsd=419).

trans, racemic8-carbamoyl-4-((4-phenylpiperidin-3-yl)amino)quinoline-3-carboxylic acid(43)

The compound was synthesized according to the procedure described forthe preparation of example 19 using trans, racemic tert-butyl3-amino-4-phenylpiperidine-1-carboxylate and4-chloro-8-cyanoquinoline-3-carboxylic acid. LC-MS (M+H=391, obsd=391).

trans, racemic4-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(44)

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-fluoro-4-methylphenyl)pyrrolidine-1-carboxylate(racemic-trans) and methyl 4-chloroquinazoline-8-carboxylate. LC-MS(M+1=365, obsd=365).

trans, racemic4-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(45)

IC₅₀p70S6K [nM]: 1.9

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate(racemic-trans) and methyl 4-chloroquinazoline-8-carboxylate. LC-MS(M+1=419, obsd=419).

4-(((3S,4R)-4-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(46)

IC₅₀p70S6K [nM]: 2.6

The compound was isolated by chiral chromatography from4-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.(trans_racemic). LC-MS (M+1=419, obsd=419).

4-(((3R,4S)-4-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(47)

IC₅₀p70S6K [nM]: 160

The compound was isolated by chiral chromatography from4-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.(trans_racemic). LC-MS (M+1=419, obsd=419).

trans, racemic4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(48)

IC₅₀p70S6K [nM]: 1.7

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate(racemic-trans) and methyl 4-chloroquinazoline-8-carboxylate. LC-MS(M+1=402, obsd=402).

4-(((3S,4R)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(49)

IC₅₀p70S6K [nM]: 60

The compound was isolated by chiral chromatography from4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(trans_racemic) LC-MS (M+1=402, obsd=402).

4-(((3R,4S)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(50)

IC₅₀p70S6K [nM]: 3

The compound was isolated by chiral chromatography4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(trans_racemic). LC-MS (M+1=402, obsd=402).

cis, racemic4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(51)

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate(Cis_racemic) and methyl 4-chloroquinazoline-8-carboxylate. LC-MS(M+1=402, obsd=402).

trans, racemic4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.(52)

IC₅₀p70S6K [nM]: 6.5

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate(racemic-trans) and methyl 4-chloroquinazoline-8-carboxylate. LC-MS(M+1=402, obsd=402).

4-(((3R,4S)-4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(53)

IC₅₀p70S6K [nM]: 66

The compound was isolated by chiral chromatography from4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(trans_racemic). LC-MS (M+1=402, obsd=402).

4-(((3R,4R)-4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(54)

IC₅₀p70S6K [nM]: 1.3

The compound was isolated by chiral chromatography from4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.(trans_racemic). LC-MS (M+1=402, obsd=402).

cis, racemic4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(55)

IC₅₀p70S6K [nM]: 9.0

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-(trifluoromethoxy)phenyl)pyrrolidine-1-carboxylate(cis-trans) and methyl 4-chloroquinazoline-8-carboxylate. LC-MS(M+1=418, obsd=418).

trans, racemic4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(56)

The IC₅₀p70S6K [nM]: 2.4

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-(trifluoromethoxy)phenyl)pyrrolidine-1-carboxylate(racemic-trans) and methyl 4-chloroquinazoline-8-carboxylate. LC-MS(M+1=418, obsd=418).

4-(((3R,4S)-4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide)(57)

IC₅₀p70S6K [nM]: 2.1

The compound was isolated by chiral chromatography from4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.(trans_racemic). LC-MS (M+1=418, obsd=418).

4-(((3R,4R)-4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(58)

IC₅₀p70S6K [nM]: 0.98

The compound was isolated by chiral chromatography from4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(trans_racemic) LC-MS (M+1=418, obsd=418).

trans, racemic4-(4-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(59)

IC₅₀p70S6K [nM]: 1.7

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(4-(trifluoromethoxy)phenyl)pyrrolidine-1-carboxylate(racemic-trans) and methyl 4-chloroquinazoline-8-carboxylate. LC-MS(M+1=418, obsd=418).

4-(((3R,4S)-4-(4-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(60)

IC₅₀p70S6K [nM]: 120

The compound was isolated by chiral chromatography from4-(4-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.(trans_racemic). LC-MS (M+1=418, obsd=418).

4-(((3S,4R)-4-(4-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(61)

IC₅₀p70S6K [nM]: 1.5

The compound was isolated by chiral chromatography from4-(4-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.(trans_racemic). LC-MS (M+1=418, obsd=418).

4-(((3S,4R)-4-(3-fluoro-4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(62)

IC₅₀p70S6K [nM]: 1.5

The compound was isolated by chiral chromatography from4-(3-fluoro-4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.(trans_racemic). LC-MS (M+1=382, obsd=382)

4-(((3R,4S)-4-(3-fluoro-4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(63)

IC₅₀p70S6K [nM]: 810

The compound was isolated by chiral chromatography from4-(3-fluoro-4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.(trans_racemic). LC-MS (M+1=382, obsd=382).

4-(((3R,4S)-4-(3-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(64)

The compound was isolated by chiral chromatography from4-(3-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(trans_racemic).LC-MS (M+1=367, obsd=367).

4-(((3R,4S)-4-(2-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(65)

IC₅₀p70S6K [nM]: 340

The compound was isolated by chiral chromatography from4-(2-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(trans_racemic). LC-MS (M+1=367, obsd=367)

4-(((3S,4R)-4-(2-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(66)

IC₅₀p70S6K [nM]: 1.4

The compound was isolated by chiral chromatography from4-(2-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(trans_racemic). LC-MS (M+1=367, obsd=367)

4-(((3S,4R)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(67)

IC₅₀p70S6K [nM]: 1.54

The compound was isolated by chiral chromatography from4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.(trans_racemic). LC-MS (M+1=352, obsd=352).

4-(((3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(68)

IC₅₀p70S6K [nM]: 48

The compound was isolated by chiral chromatography from4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.(trans_racemic). LC-MS (M+1=352, obsd=352).

trans, racemic4-(quinolin-6-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide (69)

IC₅₀p70S6K [nM]: 3.2

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(quinolin-6-yl)pyrrolidine-1-carboxylate (racemic-trans) andmethyl 4-chloroquinazoline-8-carboxylate. LC-MS (M+1=385, obsd=385).

4-(((3R,4S)-4-(quinolin-6-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(70)

IC₅₀p70S6K [nM]: 3.3

The compound was isolated by chiral chromatography from4-(quinolin-6-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(trans_racemic). LC-MS (M+1=385, obsd=385).

4-(((3S,4R)-4-(quinolin-6-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(71)

IC₅₀p70S6K [nM]: 62

The compound was isolated by chiral chromatography from4-(quinolin-6-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide. LC-MS(M+1=385, obsd=385).

4-(((3R,4S)-4-(3-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(72)

IC₅₀p70S6K [nM]: 360

The compound was isolated by chiral chromatography from compound transracemic4-(3-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=364, obsd=364).

4-(((3S,4R)-4-(3-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(73)

IC₅₀p70S6K [nM]: 6.4

The compound was isolated by chiral chromatography from compound transracemic4-(3-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=364, obsd=364).

trans, racemic4-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(74)

IC₅₀p70S6K [nM]: 8.8

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(4-fluoro-3-methylphenyl)pyrrolidine-1-carboxylate(racemic-trans) and methyl 4-chloroquinazoline-8-carboxylate. LC-MS(M+1=366, obsd=366).

4-(((3R,4S)-4-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(75)

IC₅₀p70S6K [nM]: 64

The compound was isolated by chiral chromatography from trans racemic4-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=366, obsd=366).

4-(((3S,4R)-4-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(76)

IC₅₀p70S6K [nM]: 3.4

The compound was isolated by chiral chromatography from trans racemic4-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=366, obsd=366).

trans, racemic4-(naphthalen-1-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide (77)

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(naphthalen-1-yl)pyrrolidine-1-carboxylate (racemic-trans) andmethyl 4-chloroquinazoline-8-carboxylate. LC-MS (M+1=384, obsd=384).

4-(((3R,4S)-4-(naphthalen-1-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(78)

The compound was isolated by chiral chromatography from trans racemic4-(naphthalen-1-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=384, obsd=384).

4-(((3S,4R)-4-(naphthalen-1-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(79)

IC₅₀p70S6K [nM]: 1.2

The compound was isolated by chiral chromatography from trans racemic4-(naphthalen-1-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=384, obsd=384).

4-(((3R,4S)-4-(naphthalen-2-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(80)

IC₅₀p70S6K [nM]: 24

The compound was isolated by chiral chromatography from trans racemic4-(naphthalen-2-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=384, obsd=384).

4-(((3S,4R)-4-(naphthalen-2-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(81)

The compound was isolated by chiral chromatography from its transracemic compound4-(naphthalen-2-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=384, obsd=384).

trans, racemic4-(3-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide(82)

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-fluorophenyl)pyrrolidine-1-carboxylate (racemic-trans) andmethyl 4-chloro-2-methylquinazoline-8-carboxylate. LC-MS (M+1=366,obsd=366).

4-(((3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide(83)

IC₅₀p70S6K [nM]: 160

The compound was isolated by chiral chromatography from trans racemic4-(3-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide.LC-MS (M+1=366, obsd=366).

4-(((3S,4R)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide(84)

IC₅₀p70S6K [nM]: 1.7

The compound was isolated by chiral chromatography from trans racemic4-(3-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide.LC-MS (M+1=366, obsd=366).

trans, racemic4-(3-bromophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide (85)

IC₅₀p70S6K [nM]: 1.8

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-bromophenyl)pyrrolidine-1-carboxylate (racemic-trans) andmethyl 4-chloroquinazoline-8-carboxylate. LC-MS (M+1=411/413,obsd=411/413).

cis, racemic4-(3-cyanophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide (86)

IC₅₀p70S6K [nM]: 14

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-cyanophenyl)pyrrolidine-1-carboxylate (Cis_racemic) andmethyl 4-chloroquinazoline-8-carboxylate. LC-MS (M+1=359, obsd=359).

4-(((3R,4S)-4-(3-cyanophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(87)

IC₅₀p70S6K [nM]: 81

The compound was isolated by chiral chromatography from trans racemic4-(3-cyanophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.

LC-MS (M+1=359, obsd=359).

4-(((3S,4R)-4-(3-cyanophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(88)

IC₅₀p70S6K [nM]: 2.4

The compound was isolated by chiral chromatography from trans racemic4-(3-cyanophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.

LC-MS (M+1=359, obsd=359).

trans, racemic4-(2,3-dihydrobenzofuran-5-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(89)

IC₅₀p70S6K [nM]: 3.2

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(2,3-dihydrobenzofuran-5-yl)pyrrolidine-1-carboxylate andmethyl 4-chloroquinazoline-8-carboxylate. LC-MS (M+1=376, obsd=376).

4-(((3R,4S)-4-(2,3-dihydrobenzofuran-5-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(90)

IC₅₀p70S6K [nM]: 4

The compound was isolated by chiral chromatography from its transracemic compound4-(2,3-dihydrobenzofuran-5-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=376, obsd=376).

4-(((3S,4R)-4-(2,3-dihydrobenzofuran-5-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(91)

IC₅₀p70S6K [nM]: 53

The compound was isolated by chiral chromatography from its transracemic compound4-(2,3-dihydrobenzofuran-5-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=376, obsd=376).

trans, racemic4-(3-fluoro-2-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(92)

IC₅₀p70S6K [nM]: 2

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-fluoro-2-methylphenyl)pyrrolidine-1-carboxylate(racemic-trans) and methyl 4-chloroquinazoline-8-carboxylate. LC-MS(M+1=366, obsd=366).

4-(((3R,4S)-4-(3-fluoro-2-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(93)

IC₅₀p70S6K [nM]: 1.2

The compound was isolated by chiral chromatography from trans racemic4-(3-fluoro-2-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.

LC-MS (M+1=366, obsd=366).

4-(((3S,4R)-4-(3-fluoro-2-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(94)

IC₅₀p70S6K [nM]: 52

The compound was isolated by chiral chromatography from trans racemic4-(3-fluoro-2-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.

LC-MS (M+1=366, obsd=366).

4-(((3R,4S)-4-(3-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(95)

IC₅₀p70S6K [nM]: 48

The compound was isolated by chiral chromatography from trans racemic4-(3-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.

LC-MS (M+1=367, obsd=367).

4-(((3S,4R)-4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(96)

IC₅₀p70S6K [nM]: 4.1

The compound was isolated by chiral chromatography from trans racemic4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.

LC-MS (M+1=364, obsd=364).

4-(((3R,4S)-4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(97)

IC₅₀p70S6K [nM]: 81

The compound was isolated by chiral chromatography from trans racemic4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.

LC-MS (M+1=364, obsd=364).

trans, racemic2-chlorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide(98)

IC₅₀p70S6K [nM]: 2.7

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(2-chlorophenyl)pyrrolidine-1-carboxylate and methyl4-chloro-2-methylquinazoline-8-carboxylate. LC-MS (M+1=381, obsd=381).

trans, racemic4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(99)

IC₅₀p70S6K [nM]: 0.088

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(4-chloro-3-fluorophenyl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+1=314, obsd=314).

trans, racemic4-(3-chloro-4-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(100)

IC₅₀p70S6K [nM]: 1.4

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-chloro-4-fluorophenyl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+1=314, obsd=314).

4-(((3S,4R)-4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(101)

IC₅₀p70S6K [nM]: 1.1

The compound was isolated by chiral chromatography from trans racemic4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=314, obsd=314).

trans, racemic4-(3-fluoro-4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(102)

IC₅₀p70S6K [nM]: 2.9

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-fluoro-4-methoxyphenyl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+1=311, obsd=311).

trans, racemic4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide(103)

IC₅₀p70S6K [nM]: 1.8

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(4-chloro-3-fluorophenyl)pyrrolidine-1-carboxylate and methyl4-chloro-2-methylquinazoline-8-carboxylate. LC-MS (M+1=401, obsd=401).

trans, racemic2-ethyl-4-(((3S,4R)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(104)

The compound was isolated by chiral chromatography from trans racemic4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)-2-ethylquinazoline-8-carboxamide.LC-MS (M+1=380, obsd=380).

trans, racemic4-(((3R,4S)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(105)

IC₅₀p70S6K [nM]: 420

The compound was isolated by chiral chromatography from its transracemic compound4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=388, obsd=388).

4-(((3S,4R)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(106)

IC₅₀p70S6K [nM]: 2.8

The compound was isolated by chiral chromatography from its transracemic compound4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=388, obsd=388).

trans, racemic2-ethyl-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(107)

IC₅₀p70S6K [nM]: 5.5

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-fluorophenyl)pyrrolidine-1-carboxylate and methyl4-chloro-2-ethylquinazoline-8-carboxylate. LC-MS (M+1=380, obsd=380).

2-ethyl-4-(((3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(108)

The compound was isolated by chiral chromatography from trans racemic2-ethyl-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=380, obsd=380).

trans, racemic4-(3-chloro-2-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(109)

IC₅₀p70S6K [nM]: 2.1

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-chloro-2-fluorophenyl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+1=385, obsd=385).

trans, racemic4-(naphthalen-2-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide (110)

IC₅₀p70S6K [nM]: 1.54

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(naphthalen-2-yl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+1=384, obsd=384).

trans, racemic4-(4-(methylsulfonyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(111)

IC₅₀p70S6K [nM]: 7.5

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(4-(methylsulfonyl)phenyl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+1=412, obsd=412).

4-(((3R,4S)-4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(112)

IC₅₀p70S6K [nM]: 330

The compound was isolated by chiral chromatography from trans racemiccompound4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=385, obsd=385).

trans, racemic4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)-2-ethylquinazoline-8-carboxamide(113)

The compound was synthesized according to the procedure described forthe preparation of example 2 using butyl3-amino-4-(4-chloro-3-fluorophenyl)pyrrolidine-1-carboxylate and methyl4-chloro-2-ethylquinazoline-8-carboxylate. LC-MS (M+1=413, obsd=413).

trans, racemic4-(3-chloro-5-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(114)

IC₅₀p70S6K [nM]: 1.5

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-chloro-5-fluorophenyl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+1=385, obsd=385).

trans, racemic6-fluoro-4-(((3R,4S)-4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(115)

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-chloro-5-fluorophenyl)pyrrolidine-1-carboxylate and methyl4-chloro-6-fluoroquinazoline-8-carboxylate. LC-MS (M+1=420, obsd=420).

trans, racemic4-(2,3-difluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(116)

IC₅₀p70S6K [nM]: 4.1

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(2,3-difluorophenyl)pyrrolidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+1=370, obsd=370).

trans, racemic4-(((3R,4S)-4-(3-(pyrrolidin-1-yl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(117)

IC₅₀p70S6K [nM]: 5.9

The compound was synthesized according to the procedure described forthe preparation of example 2 using tert-butyl3-amino-4-(3-(pyrrolidin-1-yl)phenyl)pyrrolidine-1-carboxylate andmethyl 4-chloroquinazoline-8-carboxylate. LC-MS (M+1=403, obsd=403).

trans, racemic4-([1,1′-biphenyl]-3-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(118)

A reaction mixture of3-[8-(aminocarbonyl)quinazolin-4-yl]amino-4-(3-bromophenyl)pyrrolidine-1-carboxylate(trans-racemic) (15.00 mg; 0.03 mmol; 1.00 eq.), phenylboronic acid(10.71 mg; 0.09 mmol; 3.00 eq.), palladium(2+) diacetate (3.94 mg; 0.02mmol; 0.60 eq.), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine(12.02 mg; 0.03 mmol; 1.00 eq.) and dipotassium carbonate (12.14 mg;0.09 mmol; 3.00 eq.) in dioxane 1 ml and water 0.1 ml in 5 ml microwavetube, was placed in microwave at 120° C. for 20 mins.

LC-MS showed conversion was completed.

Filtered, the filtrated was removed off solvent, and the residue wasadded methanol 1 ml, then

hydrogen chloride (1.00 ml; 4.00 M; 4.00 mmol; 136.64 eq.) 1 ml, stirredfor 2 h. Ic-MS showed desired.

Purified by HPLC, collected desired product.

LC-MS (M+1=411, obsd=411).

trans, racemic4-(4-fluoro-3-(pyridin-3-yl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(119)

IC₅₀p70S6K [nM]: 15

The compound was synthesized according to the procedure described forthe preparation of example 118 using tert-butyl3-((8-carbamoylquinazolin-4-yl)amino)-4-(3-chloro-4-fluorophenyl)pyrrolidine-1-carboxylate(trans_racemic) coupling with pyridin-3-ylboronic acid, then removed offboc. LC-MS (M+1=429, obsd=429).

trans, racemic4-(2-fluoro-[1,1′-biphenyl]-4-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(120)

IC₅₀p70S6K [nM]: 1.4

The compound was synthesized according to the procedure described forthe preparation of example 118 using tert-butyl3-((8-carbamoylquinazolin-4-yl)amino)-4-(4-chloro-3-fluorophenyl)pyrrolidine-1-carboxylate(trans_racemic) coupling with phenylboronic acid, then removed off boc.LC-MS (M+1=428, obsd=428).

trans, racemic4-(3-fluoro-4-(pyridin-3-yl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(121)

IC₅₀p70S6K [nM]: 6.0

The compound was synthesized according to the procedure described forthe preparation of example 118 using tert-butyl3-((8-carbamoylquinazolin-4-yl)amino)-4-(4-chloro-3-fluorophenyl)pyrrolidine-1-carboxylate(trans_racemic) coupling with pyridin-3-ylboronic acid, then removed offboc. LC-MS (M+1=429, obsd=429).

trans, racemic2-ethyl-4-((4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(122)

The compound was synthesized according to the procedure described forthe preparation of example 27 using racemic, trans racemic tert-butyl3-amino-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate and methyl4-chloro-2-ethylquinazoline-8-carboxylate. LC-MS (M+H=444, obsd=444).

trans, racemic4-(3,5-difluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(123)

IC₅₀p70S6K [nM]: 2.3

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(3,5-difluorophenyl)piperidine-1-carboxylate and methyl4-chloro-quinazoline-8-carboxylate. LC-MS (M+H=444, obsd=444).

trans, racemic1-methyl-4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide (124)

IC₅₀p70S6K [nM]: 22

A reaction mixture of4-phenylpiperidin-3-yl]aminoquinazoline-8-carboxamide trifluoroacetate(trans_racemic) (21.00 mg; 0.05 mmol; 1.00 eq.), formic acid (0.01 ml;0.11 mmol; 2.50 eq.) and formaldehyde (0.00 ml; 0.05 mmol; 1.20 eq.) inethanol was stirred at 80° C. for 3 hr, LC-MS showed clean desired.

Lyophilized, collected desired product. LC-MS (M+H=408, obsd=408).

trans, racemic2-ethyl-4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(125)

IC₅₀p70S6K [nM]: 3.9

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate and methyl4-chloro-2-ethylquinazoline-8-carboxylate. LC-MS (M+H=444, obsd=444).

trans, racemic4-(3-methoxyphenyl)piperidin-3-yl)amino)-2-methylquinazoline-8-carboxamide(126)

IC₅₀p70S6K [nM]: 4.5

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(3-methoxyphenyl)piperidine-1-carboxylate and methyl4-chloro-2-methylquinazoline-8-carboxylate. LC-MS (M+H=392, obsd=392).

trans, racemic4-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(127)

IC₅₀p70S6K [nM]: 2.0

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate and methyl4-chloro-quinazoline-8-carboxylate. LC-MS (M+H=416, obsd=416).

4-(((3S,4S)-4-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide)(128)

IC₅₀p70S6K [nM]: 230

The compound was isolated by chiral chromatography from trans racemic4-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+H=416, obsd=416).

4-(((3R,4R)-4-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(129)

IC₅₀p70S6K [nM]: 1.2

The compound was isolated by chiral chromatography from trans racemic4-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+H=416, obsd=416).

4-(((3R,4R)-4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(130)

IC₅₀p70S6K [nM]: 1.2

The compound was isolated by chiral chromatography from trans racemic4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+H=416, obsd=416).

4-(((3S,4S)-4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(131)

IC₅₀p70S6K [nM]: 160

The compound was isolated by chiral chromatography from trans racemic4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+H=416, obsd=416).

trans, racemic4-(4-fluorophenyl)piperidin-3-yl)amino)-2-methylquinazoline-8-carboxamide(132)

IC₅₀p70S6K [nM]: 5.4

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(4-fluorophenyl)piperidine-1-carboxylate and methyl 4-chloro-2methylquinazoline-8-carboxylate. LC-MS (M+H=380, obsd=380).

trans, racemic2-ethyl-4-(4-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(133)

IC₅₀p70S6K [nM]: 3.6

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(4-fluorophenyl)piperidine-1-carboxylate and methyl 4-chloro-2ethylquinazoline-8-carboxylate. LC-MS (M+H=394, obsd=394).

trans, racemic4-(4-fluorophenyl)piperidin-3-yl)amino)-2-methylquinazoline-8-carboxamide(134)

IC₅₀p70S6K [nM]: 4.2

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(4-fluorophenyl)piperidine-1-carboxylate and methyl 4-chloro-2methylquinazoline-8-carboxylate. LC-MS (M+H=380, obsd=380).

trans, racemic4-(3-methoxyphenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide (135)

IC₅₀p70S6K [nM]: 4.3

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(3-methoxyphenyl)piperidine-1-carboxylate and methyl4-chloro-quinazoline-8-carboxylate. LC-MS (M+H=378, obsd=378).

trans, racemic4-(2-fluorophenyl)piperidin-3-yl)amino)-2-methylquinazoline-8-carboxamide(136)

IC₅₀p70S6K [nM]: 210

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(2-fluorophenyl)piperidine-1-carboxylate and methyl4-chloro-2-methylquinazoline-8-carboxylate. LC-MS (M+H=380, obsd=380).

trans, racemic4-(3-fluoro-4-methylphenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(137)

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(3-fluoro-4-methylphenyl)piperidine-1-carboxylate and methyl4-chloro-quinazoline-8-carboxylate. LC-MS (M+H=380, obsd=380).

trans, racemic2-methyl-4-(((3R,4R)-4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-(138)

IC₅₀p70S6K [nM]: 2.7

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate and methyl4-chloro-2-methylquinazoline-8-carboxylate. LC-MS (M+H=430, obsd=431).

trans, racemic4-(3,4-dimethoxyphenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(139)

IC₅₀p70S6K [nM]: 18

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(3,4-dimethoxyphenyl)piperidine-1-carboxylate and methyl4-chloro-quinazoline-8-carboxylate. LC-MS (M+H=408, obsd=408).

trans, racemic4-(3-fluoro-5-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(140)

IC₅₀p70S6K [nM]: 3.1

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(3-fluoro-5-(trifluoromethyl)phenyl)piperidine-1-carboxylateand methyl 4-chloro-quinazoline-8-carboxylate. LC-MS (M+H=434,obsd=434).

trans, racemic2-methyl-4-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(141)

IC₅₀p70S6K [nM]: 2.9

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate and methyl4-chloro-2-methylquinazoline-8-carboxylate. LC-MS (M+H=430, obsd=430).

trans, racemic2-ethyl-4-(2-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(142)

IC₅₀p70S6K [nM]: 450

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(2-fluorophenyl)piperidine-1-carboxylate and methyl4-chloro-2-ethylquinazoline-8-carboxylate. LC-MS (M+H=394, obsd=394).

trans, racemic4-(4-chlorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide (143)

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(4-chlorophenyl)piperidine-1-carboxylate and methyl4-chloro-quinazoline-8-carboxylate. LC-MS (M+H=381, obsd=381).

trans, racemic2-ethyl-4-(m-tolyl)piperidin-3-yl)amino)quinazoline-8-carboxamide (144)

IC₅₀p70S6K [nM]: 5.0

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(m-tolyl)piperidine-1-carboxylate and methyl4-chloro-2-ethylquinazoline-8-carboxylate. LC-MS (M+H=390, obsd=390).

trans, racemic4-((4-(3,5-dimethylphenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide(145)

IC₅₀p70S6K [nM]: 10

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-(3,5-dimethylphenyl)piperidine-1-carboxylate and methyl4-chloroquinazoline-8-carboxylate. LC-MS (M+H=376, obsd=376).

trans, racemic6-fluoro-4-(((3R,4R)-4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide(146)

IC₅₀p70S6K [nM]: 7.1

The compound was synthesized according to the procedure described forthe preparation of example 27 using trans racemic tert-butyl3-amino-4-phenylpiperidine-1-carboxylate and methyl4-chloro-6-fluoroquinazoline-8-carboxylate. LC-MS (M+H=366, obsd=366).

4-(((3R,4S)-4-(2-fluoro-[1,1′-biphenyl]-4-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(147)

The compound was isolated by chiral chromatography from its transracemic compound4-(2-fluoro-[1,1′-biphenyl]-4-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=428, obsd=428).

4-(((3S,4R)-4-(2-fluoro-[1,1′-biphenyl]-4-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide(148)

The compound was isolated by chiral chromatography from its transracemic compound4-(2-fluoro-[1,1′-biphenyl]-4-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide.LC-MS (M+1=428, obsd=428).

Biological Activity P70S6K Enzyme Assay

P70S6K inhibitor compounds are diluted and plated in 96 well plates. Areaction mixture including the following components is then added to thecompound plate to initiate the enzyme reaction; P70S6K (3 nM, T412Emutant, Millipore) is mixed with 24 μM ATP in an assay buffer containing100 mM Hepes (pH 7.5), 5 mM MgCl2, 1 mM DTT, 0.015% Brij and 1 μM of thesubstrate peptide FITC-AHA-AKRRRLSSLRA-OH (derived from the S6 ribosomalprotein sequence, FITC=fluorescein isothiocyanate, AHA=6-aminohexanoicacid). The reaction is incubated for 90 min at 25° C., before theaddition of 10 mM EDTA to stop the reaction. The proportion of substrateand product (phosphorylated) peptide is analyzed on a Caliper LifeSciences Lab Chip 3000, using a pressure of −1.4 psi, and upstream anddownstream voltages of −3000 and −700 respectively. Product peaks areresolved before substrate peaks on the resulting chromatograms.

To assess the inhibitory potential of the compounds, IC50-values weredetermined, as shown in Chemical Synthesis section above.

The present invention having been described by the description of theinvention and the non-limiting examples above, is now defined by thespirit and scope of the following claims.

1. A compound of Formula (I)

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein: X is N or C—R³, Y is N, NH or is absent, R¹is L¹-R⁴-L²-R⁵-L³-R⁶, L¹-R⁴-L²-R⁵ or L¹-R⁴, R² is A, Hal, OH, OA, SH,CN, NH₂, NO₂, NHA, NH-L¹-Ar, NHCOA, NHCO-L¹-Ar, NHSO₂A, NHSO₂-L¹-Ar,NHCONHA, NHCONH-L¹-Ar, L¹-Ar, O-L¹-Ar, L¹-R⁴ or H, L¹ L³ each,independently of one another is a single bond, methylene, or methylsubstituted methylene, wherein the methylene, or the methyl group of themethyl substituted methylene may be unsubstituted or mono- ordisubstituted with Hal, OH, CN, NH₂, NH(LA), N(LA)₂, NO₂, COOH, N₃,ethenyl or ethynyl, and/or monosubstituted with R⁴, and in which one ortwo CH₂ groups may be replaced by an O or S atom or by an —NH—, —N(LA)-,—N(LA)COO—, —SO₂— or —NHCO— group, R³ is H, A, Hal, OH, COOH, SH, NH₂,NO₂ or CN, R⁴, R⁵, R⁶ each, independently of one another, are Ar, orcyclic A which may be mono- or disubstituted by Hal or LA, L² is —NHCO—,—NHCOO—, —NHCONH—, —NHCONA-, —NHCOA-, —O—, —S—, —NH—, —NHSO₂—, —SO₂NH—,—CONH—, —CONHCONH—, —NHCONHCO—, or -A-, Ar is a mono- or bicyclicaromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, O and/or S atomsand 5, 6, 7, 8, 9, or 10 skeleton atoms, which may be unsubstituted or,independently of one another, mono-, di- or trisubstituted by Hal, A,OH, SH, OA, NH₂, NHA, NA₂, NO₂, CN, OCN, SCN, COOH, COOA, CONH₂, CONHA,CONA₂, NHCOA, NHCONHA, NHCONH₂, NHSO₂A, CHO, COA, SO₂NH₂, SO₂A and/orSO₂Hal, and in which a ring N-atom may be substituted by an O-atom toform an N-oxide group, and in which in the case of a bicyclic aromaticcycle on of the two rings may be partly saturated, A is unbranched orbranched linear or cyclic alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms,in which one or two CH₂ groups may be replaced by an O or S atom and/orby an —NH—, —CO—, —NHCOO—, —NHCONH—. —N(LA)-, —CONH—, —NHCO— or —CH═CH—group, and in which 1-3 H atoms may be replaced by Hal, and in which oneor two CH₃ groups may be replaced by OH, SH, NH₂, NH(LA), N(LA)₂,NHCOOH, NHCONH₂ or CN, LA is unbranched or branched, linear alkyl having1, 2, 3 or 4 C atoms, wherein 1, 2 or 3 H atoms may be replaced by Haland Hal is F, Cl, Br or I.
 2. Compounds according to claim 1 andpharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein: X is N, Y is NH, R¹ is L¹-R⁴-L²-R⁵, R²′ isLA, Hal, OH, O(LA), SH, CN, NH₂, NO₂, NH(LA), NHCO(LA), NHSO₂(LA),NHCONH(LA) or H, L¹ is methyl substituted methylene, wherein the methylgroup of the methyl substituted methylene is monosubstituted with NH₂ orNH(LA), N(LA)₂, or cyclic A which may be mono- or disubstituted by Halor LA, R⁴,R⁵ is a monocyclic aromatic homo- or heterocycle having 0, 1or 2 N, O and/or S atoms and 5 or 6 skeleton atoms, which may beunsubstituted or, independently of one another, mono-, di- ortrisubstituted by Hal, A, OH, SH, OA, NH₂, NHA, NA₂, NO₂, CN, OCN, SCN,COOH, COOA, CONH₂, CONHA, CONA₂, NHCOA, NHCONHA, NHCONH₂, NHSO₂A, CHO,COA, SO₂NH₂, SO₂A and/or SO₂Hal, A is unbranched or branched linear orcyclic alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one ortwo CH₂ groups may be replaced by an O or S atom and/or by an —NH—,—CO—, —NHCOO—, —NHCONH—. —N(LA)-, —CONH—, —NHCO— or —CH═CH— group, andin which 1-3 H atoms may be replaced by Hal, and in which one or two CH₃groups may be replaced by OH, SH, NH₂, NH(LA), N(LA)₂, NHCOOH, NHCONH₂or CN, L² is —NHCO—, —NHCOO—, —NHCONH—, —NHCONA-, —NHCOA-, —O—, —S—,—NH—, —NHSO₂—, —SO₂NH—, —CONH—, —CONHCONH—, —NHCONHCO—, or -A-, LA isunbranched or branched, linear alkyl having 1, 2, 3 or 4 C atoms,wherein 1, 2 or 3 H atoms may be replaced by Hal and Hal is F, Cl, Br orI.
 3. The compound of Formula (II)

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein: X is N or C—R³, R² is A, Hal, OH, OA, SH, CN,NH₂, NO₂, NHA, NH-L¹-Ar, NHCOA, NHCO-L¹-Ar, NHSO₂A, NHSO₂-L¹-Ar,NHCONHA, NHCONH-L¹-Ar, L¹-Ar, O-L¹-Ar, L¹-R⁴, R³ is H, A, Hal, OH, COOH,SH, NH₂, NO₂ or CN, Y′ is CH2 or NH such that when Y′ is NH, Z is CH2(or absent) and when Y′ is CH2, Z is NH, Z is CH2, NH or is absent suchthat when Z is CH2 (or absent), Y is NH and when Z is NH, Y is CH2, andZ′ Ar, alkyl, halogen, OR, NRR, CF3, CN, OCF3, SR, H (mono, di, ortri-substituted with any above combination) and pharmaceuticallyacceptable salts, solvates, solvates of salts, or prodrugs thereof. 4.The compound of Formula (III)

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein: X is N or C—R³, R² is A, Hal, OH, OA, SH, CN,NH₂, NO₂, NHA, NH-L¹-Ar, NHCOA, NHCO-L¹-Ar, NHSO₂A, NHSO₂-L¹-Ar,NHCONHA, NHCONH-L¹-Ar, L¹-Ar, O-L¹-Ar, R³ is H, A, Hal, OH, COOH, SH,NH₂, NO₂ or CN, Y′ is CH2 or NH such that when Y′ is NH, Z is CH2 (orabsent) and when Y′ is CH2, Z is NH, Z is CH2, NH or is absent such thatwhen Z is CH2 (or absent), Y is NH and when Z is NH, Y is CH2, and Z′Ar, alkyl, halogen, OR, NRR, CF3, CN, OCF3, SR, H (mono, di, ortri-substituted with any above combination) and pharmaceuticallyacceptable salts, solvates, solvates of salts, or prodrugs thereof. 5.The compound according to claim 1, wherein the compound is selected fromthe group consisting of: trans racemic4-((4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;trans racemic4-((4-phenylpyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-((4-(2-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-((4-(4-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-((4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-((4-(3-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide,4-((4-(2-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;trans, racemic4-((4-(3-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;trans, racemic4-((4-(2-chloro-6-fluorophenyl)pyrrolidin-3-yl)amino)-quinazoline-8-carboxamide;trans, racemic4-((4-(3-bromophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;trans, racemic4-((4-(3-fluorophenyl)-1-methylpyrrolidin-3-yl)amino)quinazoline-8-carboxamide;trans, racemic4-((-4-(naphthalen-2-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;trans, racemic4-((4-(naphthalen-1-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;6-methyl-4-((4-phenylpyrrolidin-3-yl)amino)quinazoline-8-carboxamide,2-methyl-4-((4-phenylpyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-((4-(4-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;4-((4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;4-((4-(4-fluorophenyl)-1-methylpyrrolidin-3-yl)amino)quinoline-8-carboxamide;4-((4-phenylpyrrolidin-3-yl)amino)quinoline-8-carboxamide;4-((4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide;4-((4-(2-fluorophenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide;4-((4-(2-methoxyphenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide;4-((4-(3-methoxyphenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide;4-((4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)quinoline-8-carboxamide;trans-4-(4-Phenylcarbamoyl-pyrrolidin-3-ylamino)-quinazoline-8-carboxylicacid amide; trans, racemic4-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide; racemic,trans4-((4-(3-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;cis, racemic 4-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide;trans, racemic4-((4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;trans, racemic4-((4-(m-tolyl)piperidin-3-yl)amino)quinazoline-8-carboxamide; trans,racemic4-((4-(4-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;trans, racemic tert-butyl3-amino-4-(4-chlorophenyl)piperidine-1-carboxylate; racemic, trans,Benzyl 3-amino-4-(3-fluoro-4-methylphenyl)piperidine-1-carboxylate;trans, racemic Benzyl3-((8-carbamoylquinazolin-4-yl)amino)-4-(3-fluoro-4-methylphenyl)piperidine-1-carboxylate;racemic, trans4-((4-(3-fluoro-4-methylphenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;trans, racemic4-((4-(3-fluorophenyl)piperidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;trans, racemic2-ethyl-4-((4-(3-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;trans, racemic2-ethyl-4-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide;trans, racemic2-methyl-4-((4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide;trans, racemic 4-((4-phenylpiperidin-3-yl)amino)quinoline-8-carboxamide;trans, racemic Ethyl8-carbamoyl-4-(4-phenylpiperidin-3-yl)amino)quinoline-3-carboxylate;trans, racemic8-carbamoyl-4-((4-phenylpiperidin-3-yl)amino)quinoline-3-carboxylicacid;4-(3-fluoro-4-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4R)-4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4R)-4-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(4-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(4-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(4-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(3-fluoro-4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(3-fluoro-4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(3-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(2-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(2-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(quinolin-6-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(quinolin-6-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(quinolin-6-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(3-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(3-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(4-fluoro-3-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(naphthalen-1-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(naphthalen-1-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(naphthalen-1-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(naphthalen-2-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(naphthalen-2-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;4-(((3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;4-(((3S,4R)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;4-(3-bromophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-cyanophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(3-cyanophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(3-cyanophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(2,3-dihydrobenzofuran-5-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(2,3-dihydrobenzofuran-5-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(2,3-dihydrobenzofuran-5-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-fluoro-2-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(3-fluoro-2-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(3-fluoro-2-methylphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(3-chlorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;2-chlorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-chloro-4-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-fluoro-4-methoxyphenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;2-ethyl-4-(((3S,4R)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;2-ethyl-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;2-ethyl-4-(((3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-chloro-2-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(naphthalen-2-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(4-(methylsulfonyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)amino)-2-ethylquinazoline-8-carboxamide;4-(3-chloro-5-fluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;6-fluoro-4-(((3R,4S)-4-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(2,3-difluorophenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(3-(pyrrolidin-1-yl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-([1,1′-biphenyl]-3-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(4-fluoro-3-(pyridin-3-yl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(2-fluoro-[1,1′-biphenyl]-4-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-fluoro-4-(pyridin-3-yl)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;2-ethyl-4-((4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-(3,5-difluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;1-methyl-4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide;2-ethyl-4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-methoxyphenyl)piperidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;4-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4S)-4-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4R)-4-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4R)-4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4S)-4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-(4-fluorophenyl)piperidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;2-ethyl-4-(4-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-(4-fluorophenyl)piperidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;4-(3-methoxyphenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-(2-fluorophenyl)piperidin-3-yl)amino)-2-methylquinazoline-8-carboxamide;4-(3-fluoro-4-methylphenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;2-methyl-4-(((3R,4R)-4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-(3,4-dimethoxyphenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-(3-fluoro-5-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;2-methyl-4-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;2-ethyl-4-(2-fluorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-(4-chlorophenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;2-ethyl-4-(m-tolyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;4-((4-(3,5-dimethylphenyl)piperidin-3-yl)amino)quinazoline-8-carboxamide;6-fluoro-4-(((3R,4R)-4-phenylpiperidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3R,4S)-4-(2-fluoro-[1,1′-biphenyl]-4-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide;4-(((3S,4R)-4-(2-fluoro-[1,1′-biphenyl]-4-yl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamideand pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof.
 6. A pharmaceutical composition comprising a compoundaccording to claim 1, or a pharmaceutically acceptable salt, solvate,solvate of a salt, or prodrug thereof, as active ingredient, togetherwith a pharmaceutically acceptable carrier.
 7. A compound of claim 1, ora pharmaceutically acceptable salt, solvate, solvate of a salt, orprodrug thereof, for use as a medicament.
 8. A compound of claim 1, or apharmaceutically acceptable salt, solvate, solvate, solvate of a salt,or prodrug thereof, for treating hyperproliferative diseases.
 9. Thecompound of claim 8, or a pharmaceutically acceptable salt, solvate,solvate of a salt, or prodrug thereof, wherein the disease is selectedfrom the group consisting of cancer, inflammation, pancreatitis orkidney disease, pain, benign hyperplasia of the skin, restenosis,prostate, diseases related to vasculogenesis or angiogenesis, tumorangiogenesis, skin diseases selected from psoriasis, eczema, andsclerodema, diabetes, diabetic retinopathy, retinopathy of prematurity,age-related macular degeneration, hemangioma, glioma, melanoma andKaposi's sarcoma.
 10. Use of a compound of claim 1, or apharmaceutically acceptable salt, solvate, solvate of a salt, or prodrugthereof, for the preparation of a medicament for the treatment ofhyperproliferative diseases.
 11. Use according to claim 10 wherein thedisease is selected from the group consisting of cancer, inflammation,pancreatitis or kidney disease, pain, benign hyperplasia of the skin,restenosis, prostate, diseases related to vasculogenesis orangiogenesis, tumor angiogenesis, skin diseases selected from psoriasis,eczema, and sclerodema, diabetes, diabetic retinopathy, retinopathy ofprematurity, age-related macular degeneration, hemangioma, glioma,melanoma and Kaposi's sarcoma.
 12. A method for treatinghyperproliferative diseases, comprising administering to a subject acompound of claim 1, or a pharmaceutically acceptable salt, solvate,solvate of a salt, or prodrug thereof.
 13. The method of claim 12,wherein the disease is selected from the group consisting of cancer,inflammation, pancreatitis or kidney disease, pain, benign hyperplasiaof the skin, restenosis, prostate, diseases related to vasculogenesis orangiogenesis, tumor angiogenesis, skin diseases selected from psoriasis,eczema, and sclerodema, diabetes, diabetic retinopathy, retinopathy ofprematurity, age-related macular degeneration, hemangioma, glioma,melanoma and Kaposi's sarcoma.
 14. Set (kit) consisting of separatepacks of: a) an effective amount of a compound according to claim 1 or apharmaceutically acceptable salt, solvate, solvate of a salt, or prodrugthereof, and b) an effective amount of a further medicament activeingredient.
 15. Process for the manufacture of compounds of Formula (I),wherein X is N and Y is NH, and all other substituents have the meaningas defined for Formula (I) in claim 1, wherein a carboxylic acid esterof Formula (IV)

is reacted with a compound of Formula (V)

to yield a compound of Formula (VI)

which is finally converted into the carboxylic amide of Formula (I)